β3 adrenergic receptor agonists and uses thereof

ABSTRACT

The instant invention provides β 3  adrenergic receptor agonists of structural Formula (I),                    
     the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, wherein Ar, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, and Y, are as defined herein. The invention further provides intermediates useful in the preparation of the compounds of Formula (I), to combinations of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, with anti-obesity agents; to pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, or pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, and anti-obesity agents; and methods of treating β 3  adrenergic receptor-mediated diseases, conditions, or disorders in a mammal which methods comprise administering to the mammal an effective amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutical composition thereof; or a combination of a compound of Formula (I), a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and an anti-obesity agent, or a pharmaceutical composition thereof.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/242,274 filed Oct. 20, 2000.

FIELD OF THE INVENTION

The present invention relates to compounds of Formula (I) depictedhereinbelow, which compounds are β₃ adrenergic receptor agonists and,accordingly, have utility as, inter alia, hypoglycemic, and anti-obesityagents.

The invention further relates to intermediates useful in the preparationof the compounds of Formula (I); to combinations of the compounds ofFormula (I) with anti-obesity agents; to pharmaceutical compositionscomprising such compounds and combinations; and to methods of using thecompounds, combinations, and pharmaceutical compositions in thetreatment of β₃ adrenergic receptor-mediated diseases, conditions, ordisorders in a mammal. The compounds and combinations of the inventionalso possess utility for increasing the content of lean meat in edibleanimals, i.e. ungulate animals such as cattle, swine, and the like, aswell as poultry.

The compounds and combinations of this invention further possess utilityin the treatment of intestinal motility disorders, depression, prostatedisease, dyslipidemia, and airway inflammatory disorders.

BACKGROUND OF THE INVENTION

The disease diabetes mellitus is characterized by metabolic defects inthe production and utilization of carbohydrates which result in thefailure to maintain appropriate blood sugar levels. The results of thesedefects include, inter alia, elevated blood glucose or hyperglycemia.Research in the treatment of diabetes has centered on attempts tonormalize fasting and postprandial blood glucose levels. Currenttreatments include administration of exogenous insulin, oraladministration of drugs and dietary therapies.

Two major forms of diabetes mellitus are recognized. Type 1 diabetes, orinsulin-dependent diabetes mellitus (IDDM), is the result of an absolutedeficiency of insulin, the hormone that regulates carbohydrateutilization. Type 2 diabetes, or non-insulin-dependent diabetes mellitus(NIDDM), often occurs with normal, or even elevated, levels of insulinand appears to be the result of the inability of tissues to respondappropriately to insulin. Most Type 2 diabetic patients are also obese.

The compounds of the invention effectively lower blood glucose levelswhen administered orally to mammals with hyperglycemia or diabetes.

Obesity constitutes a major health risk that leads to mortality andincidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia.In the United States, more than 50% of the adult population isoverweight, and almost 25% of the population is considered to be obese.The incidence of obesity is increasing in the United States at athree-percent cumulative annual growth rate. While the vast majority ofobesity occurs in the United States and Europe, the prevalence ofobesity is also increasing in Japan. Furthermore, obesity is adevastating disease which can also wreak havoc on an individual's mentalhealth and self-esteem, which can ultimately affect a person's abilityto interact socially with others. Unfortunately, the precise etiology ofobesity is complex and poorly understood, and societal stereotypes andpresumptions regarding obesity only tend to exacerbate the psychologicaleffects of the disease. Because of the impact of obesity on society ingeneral, much effort has been expended in efforts to treat obesity,however, success in the long-term treatment and/or prevention thereofremains elusive.

The compounds, pharmaceutical compositions, and combinations of theinvention also reduce body weight or decrease weight gain whenadministered to a mammal. The ability of the compounds to affect weightgain is due to activation of β₃ adrenergic receptors which stimulate themetabolism of adipose tissue.

β-Adrenergic agents have been generally classified into β₁, β₂, and β₃receptor-specific subtypes. Agonists of β-receptors promote theactivation of adenyl cyclase. Activation of β₁ receptors invokes anincrease in heart rate while activation of β₂ receptors induces smoothmuscle tissue relaxation which produces a drop in blood pressure and theonset of skeletal muscle tremors. Activation of β₃ receptors is known tostimulate lipolysis (e.g., the breakdown of adipose tissue triglyceridesinto glycerol and fatty acids) and metabolic rate (energy expenditure),thereby promoting the loss of fat mass. Accordingly, compounds thatstimulate β₃ receptors are therefore useful as anti-obesity agents, andcan be further used to increase the content of lean meat in edibleanimals. In addition, compounds that are β₃ receptor agonists havehypoglycemic activity, however, the precise mechanism of this effect ispresently unknown.

Until recently, β₃ adrenergic receptors were thought to be foundpredominantly in adipose tissue, however, β₃ receptors are now known tobe located in such diverse tissues as the intestine, (J. Clin. Invest.,91, 344 (1993)) and the brain Eur. J. (Pharm., 219, 193 (1992)).Stimulation of β₃ receptors has also been demonstrated to inducerelaxation of smooth muscle in the colon, trachea, and bronchi. See, forexample, Life Sciences, 44, 1411 (1989), Br. J. Pharm., 112, 55 (1994),and Br. J. Pharmacol., 110, 1311 (1993). Furthermore, stimulation of β₃receptors has also been found to induce relaxation ofhistamine-contracted guinea pig ileum. See, for example, J. Pharm. Exp.Ther., 260, 1, 192 (1992).

The β₃ receptor is also expressed in the human prostate (J. Clin.Invest., 91, 344 (1993). Because stimulation of the β₃ receptor causesrelaxation of smooth muscles that have been shown to express the β₃receptor, i.e. intestinal smooth muscle, one of ordinary skill in theart would also predict relaxation of prostate smooth muscle. Therefore,β₃ agonists are useful in the treatment or prevention of prostatedisease.

Commonly assigned U.S. Pat. No. 5,977,124 discloses certain β₃adrenergic receptor agonists having utility in the treatment of, interalia, hypoglycemia and obesity.

U.S. Pat. No. 5,776,983 discloses certain catecholamines useful asβ₃-agonists.

U.S. Pat. No. 5,030,640 discloses certain α-heterocyclic ethanol aminoalkyl indoles, which are useful as growth promoters, bronchodilators,anti-depressants, and anti-obesity agents.

U.S. Pat. No. 5,019,578 discloses certain α-heterocyclic ethanolaminesuseful as growth promoters.

U.S. Pat. No. 4,478,849 discloses pharmaceutical compositions comprisingcertain ethanolamine derivatives and methods of using such compositionsin the treatment of obesity and/or hyperglycaemia.

U.S. Pat. No. 4,358,455 discloses certain heterocyclic compounds of thestructural formula Het—CHOH—CH₂—NH—aralkyl, which compounds are usefulfor treating glaucoma and cardiovascular disease.

European Patent Application Publication No. 0 516 349, published Dec. 2,1992, discloses certain 2-hydroxyphenethyl amines which possessanti-obesity, hypoglycemic, and related utilities.

U.S. Pat. No. 5,153,210 discloses certain heterocyclic compounds of theformula R^(o)—X—CH(OH)—CH₂—N(R¹)—C(R²)(R³)—(CH₂)_(n)—Y—A—R⁴—R⁵ whichcompounds are useful as anti-obesity and anti-hyperglycaemic agents.

PCT International Patent Application Publication No. WO 99/65877,published Dec. 23, 1999, discloses heterocyclic compounds having thestructural formula

which compounds are useful for the treatment of diseases susceptible toamelioration by administration of an atypical beta-adrenoceptor agonist.

SUMMARY OF THE INVENTION

The instant invention provides β₃ adrenergic receptor agonists ofstructural Formula (I),

the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of the compounds, stereoisomers and prodrugs, whereinAr, R, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, X, and Y are as definedhereinbelow.

In another aspect, the invention provides intermediates useful in thepreparation of the compounds of Formula (I); to combinations of thecompounds of Formula (I), the stereoisomers and prodrugs thereof, andthe pharmaceutically acceptable salts of the compounds, stereoisomersand prodrugs, with anti-obesity agents; to pharmaceutical compositionscomprising the compounds of Formula (I), the stereoisomers and prodrugsthereof, and the pharmaceutically acceptable salts of the compounds,stereoisomers and prodrugs, or pharmaceutical compositions comprisingthe compounds of Formula (I), the stereoisomers and prodrugs thereof,and the pharmaceutically acceptable salts of the compounds,stereoisomers and prodrugs, and anti-obesity agents; and methods oftreating β₃ adrenergic receptor-mediated diseases, conditions, ordisorders in a mammal which methods comprise administering to the mammalan effective amount of a compound of Formula (I), a stereoisomer orprodrug thereof, or a pharmaceutical composition thereof; or acombination of a compound of Formula (I), a pharmaceutically acceptablesalt of the compound, stereoisomer, or prodrug, and an anti-obesityagent, or a pharmaceutical composition thereof, acceptable salt of thecompound, stereoisomer, or prodrug, and an anti-obesity agent, or apharmaceutical composition thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides β₃ adrenergic receptor agonists ofstructural Formula (I),

the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of said compounds, stereoisomers and prodrugs, wherein:

Ar is pyridyl, oxazolyl, thiazolyl, or phenyl;

R is hydrogen, hydroxy, oxo, halogen, —CF₃, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —(C₃-C₈)cycloalkyl, —NR₉R₁₀, —NR₉SO₂R₁₀, —NR₉COR₁₀, or—SO₂R₉;

R₁ is hydrogen, —(C₁-C₆)alkyl, halogen, —(C₁-C₆)alkoxy, or hydroxy;

R₂, R₃, R₄ are, independently, hydrogen, or —(C₁-C₆)alkyl;

R₅ is a 5- or 6-membered ring heterocycle having from 1 to 4 heteroatomsselected from the group consisting of oxygen, sulfur, or nitrogen;

R₆ and R₇ are, independently, hydrogen, halogen, cyano, oxo,—(C₁-C₆)acyl, —CO₂R₉, —NR₉R₁₀, hydroxy, —(C₁-C₆)alkoxy, —CONR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or —SO₂R₉; —(C₁-C₆)alkyl, optionally substitutedwith —(C₃-C₈)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy,—(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀,—SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; —(C₃-C₈)cycloalkyl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; aryl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; or heterocycle,optionally substituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen,aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle;

R₈ is hydrogen, —(C₁-C₄)alkyl, or halogen; and

R₉ and R₁₀ are, independently, hydrogen, —(C₁-C₆)alkyl, alkylalkoxy,—(C₃-C₈)cycloalkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, aryl, orheterocycle;

X is a direct bond or oxygen; and

Y is a direct bond, —(C₁-C₆)alkyl, —OCH₂—, —CH₂O—, or oxygen; providedthat:

(i) when Ar is phenyl, R is —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or —SO₂R₉; and

(ii) when Ar is phenyl, —NR₉SO₂R₁₀, and R₆ and R₇ are both hydrogen,then R₅ is not imidazolyl.

The compounds of Formula (I), the stereoisomers and prodrugs thereof,and the pharmaceutically acceptable salts of the compounds,stereoisomers and prodrugs, wherein Ar, R, R₁, R₂, R₃, R₄, R₅, R₆, R₇,R₈, X, and Y are as defined hereinabove, that are extant in the(R)-stereo configuration, designated by Formula (I′) hereinbelow, areespecially preferred.

A first generally preferred subgroup of the compounds of Formula (I),the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of the compounds, stereoisomers and prodrugs, comprisesthose compounds wherein Ar is pyridyl; R, R₁, R₂, R₃, R₄ and R₈, arehydrogen; X is oxygen; Y is a direct bond; and R₅ is a five- orsix-membered ring heterocycle selected from the group consisting ofdihydropyridazinonyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinonyl, pyridazinyl,pyridyl, pyrimidinonyl, pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl,triazinyl, and triazolyl,

Among the first generally preferred subgroup of the compounds of Formula(I), the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of the compounds, stereoisomers and prodrugs, thefollowing compounds are particularly preferred:

(R)-2-{2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-6-{4-[2-(2-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one;

(R)-2-[2-(4-imidazol-1-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(5-methyl-oxazol4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxyl-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxyl]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol

(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl)-phenoxy}-ethylamino)-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;and

(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol.

Among the first generally preferred subgroup of the compounds of Formula(I), the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of the compounds, stereoisomers and prodrugs, thefollowing compounds are especially preferred:

(R)-2-{2-[4-(ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;and

(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol.

A second generally preferred subgroup of the compounds of Formula (I),the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of said compounds, stereoisomers and prodrugs,comprises those compounds wherein Ar is phenyl; R is —NR₉SO₂R₁₀; R₁ ishydrogen, hydroxy, or halogen; R₂, R₃, R₄, and R₈, are hydrogen; X isoxygen and Y is a direct bond; and R₅ is a five- or six-membered ringheterocycle selected from the group consisting of dihydropyridazinonyl,imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinonyl, pyridazinyl, pyridyl,pyrimidinonyl, pyrimidyl, thiadiazolyl, thiazolinyl, thiazolyl,triazinyl, and triazolyl.

Among the second generally preferred subgroup of the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers andprodrugs, the following compounds are particularly preferred:

(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;and

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide.

Among the second generally preferred subgroup of the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers andprodrugs, the following compounds are especially preferred:

(R)-N-[2-chloro-5-(2-{4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(2-{4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-(4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;and

(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-sulfonamide.

The instant invention further provides certain amine intermediatesuseful in the preparation of the compounds of Formula (I) which amineintermediates comprise compounds having the structural formula

and the acid addition salts thereof, wherein:

R₅ is a 5- or 6-membered ring heterocycle selected from the groupconsisting of isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl,oxazolyl, pyrazolyl, pyridazinyl, thiadiazolyl, thiazolinyl, thiazolyl,and triazinyl;

R₆ and R₇ are, independently, hydrogen, halogen, cyano, oxo,—(C₁-C₆)acyl, —CO₂R₉, —NR₉R₁₀, hydroxy, —(C₁-C₆)alkoxy, —CONR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or —SO₂R₉; —(C₁-C₆)alkyl, optionally substitutedwith —(C₃-C₈)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy,—(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀,—SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; —(C₃-C₈)cycloalkyl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; aryl, optionallysubstituted with —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, halogen, aryl,—(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle; or heterocycle,optionally substituted with —(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, halogen,aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy, —NR₉R₁₀,—NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle;

R₈ is hydrogen, —(C₁-C₄)alkyl, or halogen; and

Y is a direct bond, or —CH₂—.

Generally preferred amine intermediates of the structural formula shownhereinabove comprise those compounds selected from the group consistingof:

2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamine;

2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2-ethyl-oxazol-4-yl-4)-phenoxy]-ethylamine;

2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamine;

2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamine;

2-[4-(4-ethyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy}-ethylamine;

2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamine;

2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamine;

2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamine;

2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamine;

2-(3-methyl-4-oxazol-4-yl)-phenoxy]-ethylamine;

2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamine;

2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamine;

2-[4-(2-methyl-thiazol-4-yl)-phenoxyl-ethylamine;

2-[4-(4-methyl-thiazol-2-yl)-phenoxyl-ethylamine;

2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamine;

2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamine;

2-(4-[1,3,5]oxadiazol-2-yl-phenoxy)-ethylamine;

2-(4-oxazol-2-yl-phenoxy)-ethylamine;

2-(4-oxazol-4-yl-phenoxy)-ethylamine;

2-(4-oxazol-5-yl-phenoxy)-ethylamine;

2-[4-(2-phenethyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamine;

2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamine;

2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamine;

2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-(4-pyrazol-1-yl-phenoxy)-ethylamine;

2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamine;

2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamine;

2-4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamine;

2-(4-[1,2,3]thiadiazol-5-yl-phenoxy)-ethylamine;

2-(4-thiazol-2-yl-phenoxy)-ethylamine;

2-(4-thiazol-4-yl-phenoxy)-ethylamine;

2-[4-(2-thiophen-2-ylthiazol-4-yl)-phenoxy]-ethylamine;

2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamine;

2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamine;

2-{4-[-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy-ethylamine;

2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamine; and

2-[4-(5-trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]-ethylamine; and theacid addition salts thereof.

The compounds and intermediates of the present invention may be namedaccording to either the IUPAC (International Union for Pure and AppliedChemistry) or CAS (Chemical Abstracts) nomenclature systems.

The carbon atom content of the various hydrocarbon-containing moietiesmay be indicated by a prefix designating the minimum and maximum numberof carbon atoms in the moiety, i.e. the prefix (C_(a)-C_(b)) indicates amoiety of the integer “a” to “b” carbon atoms, inclusive. Thus, forexample, (C₁-C₃)alkyl refers to alkyl of one to three carbon atomsinclusive, or methyl, ethyl, propyl, isopropyl, and all isomeric forms,and straight and branched chain forms thereof.

The term “alkyl” denotes a straight or branched chain hydrocarbon.Representative examples of alkyl groups comprise methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, and hexyl.

The term “alkoxy” denotes an alkyl group bonded to an oxygen atom.Representative examples of alkoxy groups include methoxy, ethoxy,tert-butoxy, propoxy, and isobutoxy.

The term “halogen” or “halo” denotes a radical derived from chlorine,fluorine, bromine, or iodine.

The term “cycloalkyl” denotes a cyclic hydrocarbon. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl. It is also possible for the cycloalkylgroup to have one or more double or triple bonds, or a combination ofdouble bonds and triple bonds, but is not aromatic. Examples ofcycloalkyl groups having a double or triple bond include cyclopentenyl,cyclohexenyl, cyclohexadienyl, cyclobutadienyl, and the like. It is alsonoted that the term cycloalkyl includes polycyclic compounds such asbicyclic or tricyclic compounds.

The term “acyl” denotes a group derived from an organic acid (—COOH) byremoval of of the hydroxy group (—OH).

The term “aryl” denotes a cyclic, aromatic hydrocarbon. Examples of arylgroups include phenyl, naphthyl, and biphenyl. The aryl group can besubstituted or unsubstituted.

The term “heteroatom” includes oxygen, nitrogen, sulfur, and phosphorus.

The term “heterocycle”, as employed within the definitions of R₅, R₆,R₇, R₉, and R₁₀, denotes a cyclic, aromatic or non-aromatic hydrocarbonradical in which between one and four of the carbon atoms therein havebeen replaced with heteroatoms. If the heterocyclic radical containsmore than one heteroatom, the individual heteroatoms may be the same ordifferent. Representative examples of five- and six-membered aromatic,or non-aromatic, heterocyclic groups include chromenyl,dihydropyridazinonyl, dihydropyridazinyl, furyl, imidazolidinyl,imidazolyl, indazolyi, indolizinyl, indolyl, isobenzofuranyl,isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl,naphthyridinyl, oxadiazolyl, oxazinyl, oxazolinyl, oxazolyl,phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazolyl,pyridazinonyl, pyridazinyl, pyridyl, pyrimidinonyl, pyrimidyl,pyrrolidinyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl,thiadiazolyl, thiazolinyl, thiazolyl, thienyl, thiomorpholinyl,triazolyl, and xanthenyl. It is to be understood that the heterocyclicradical may be bonded to another group in more than one way. If noparticular bonding arrangement is specified, then all possiblearrangements are intended. For example, the term “pyridyl” includes 2-,3-, or 4-pyridyl, and the term “thienyl” includes 2-, or 3-thienyl.

Specific representative examples of five- to six-membered aromatic, ornon-aromatic, heterocyclic groups are 1,4-dioxanyl, 3H-1,2,3-dioxazolyl,1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2-dioxinyl,1,3-dioxinyl, 1,3-dioxolanyl, 1,4-dithianyl, 1,2-dithiolyl,1,3-dithiolyl, 2-imidazolinyl, 2H-imidazolyl, o-isoxazinyl,p-isoxazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl,6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl,1,2,5-oxathiazinyl, 1,4-oxazinyl, 1,2,5-oxathiazinyl,1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl, 5H-1,2,5-oxathiazolyl,3H-1,2-oxathiolyl, 1,3-oxathiolyl, 2H-pyranyl, 4H-pyranyl,2-pyrazolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1,3,4-thiadiazolyl,1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, and 1,3,5-trithianyl.

It is also noted that the heterocyclic radical can comprise more thanone ring. For example, a naphthyl group is a representative of a fusedbicyclic ring system. It is also intended that the present inventioninclude ring groups that have bridging atoms, or ring groups having aspiro-orientation. For example, the term “spirocycloalkyl” means acycloalkyl ring having a spiro union (the union formed by a single atomwhich is the only common member of the rings). In addition, it isunderstood that, unless specifically noted otherwise, all suitableisomers of the cyclic ring groups are included herein.

Exemplary bicyclic rings consisting of two fused partially saturated,fully saturated, or fully unsaturated five- and/or six-membered rings,taken independently, optionally having one to four heteroatoms areanthranilyl, benzimidazolyl, benzofuryl, 2H-1-benzopyranyl,benzothiazolyl, benzo[b]thienyl, benzo[c]thienyl, 2H-1,3-benzoxazinyl,2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl,2H-1,2-benzoxazinyl, 4H-1,4-benzoxazinyl, benzoxazolyl, cinnolinyl,cyclopenta[b]pyridinyl, decalinyl, indazolyl, indenyl, indolinyl,indolizinyl, indolyl, 1H-indoxazinyl, isobenzofuryl, isoindenyl,isoindolyl, isoquinolinyl, naphthyl, naphthyridinyl, phthalazinyl,1,8-pteridinyl, purinyl, pyrano[3,4-b]pyrrolyl, pyrido[3,2-b]-pyridinyl,pyrido[3,4-b]-pyridinyl, pyrido[4,3-b]-pyridinyl, quinazolinyl,quinolinyl, quinoxalinyl, and tetralinyl.

The term “substituted” means that a hydrogen atom on a molecule has beenreplaced with a different atom or molecule. The atom or moleculereplacing the hydrogen atom is denoted as a “substituent.”

The phrase “therapeutically effective amount” means an amount of acompound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, which amount attenuates, ameliorates, or eliminates one or moresymptoms of a particular disease, condition, or disorder, or prevents ordelays the onset of one or more symptoms of a particular disease,condition, or disorder.

The term “mammal” means animals including, for example, dogs, cats,cows, sheep, horses, and humans. Preferred mammals include humans,including members of both male and female sexes.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “treating”, “treat”, or “treatment” embrace both preventative,i.e., prophylactic, and palliative treatment.

In another aspect of the instant invention, the compounds of Formula(I), the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of the compounds, stereoisomers and prodrugs, can beemployed in combination with an anti-obesity agent.

The anti-obesity agent is preferably selected from the group consistingof an apolipoprotein-B secretion/microsomal triglyceride transferprotein (apo-B/MTP) inhibitor, an MCR-4 agonist, a cholecystokinin-A(CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), asympathomimetic agent, a serotoninergic agent (such as fenfluramine ordexfenfluramine), a dopamine agonist (such as bromocriptine), amelanocyte-stimulating hormone receptor analog, a cannabinoid receptorantagonist, a melanin concentrating hormone antagonist, leptin (the OBprotein), a leptin analog, a leptin receptor agonist, a galaninantagonist, a lipase inhibitor (such as tetrahydrolipstatin, i.e.orlistat), an anorectic agent (such as a bombesin agonist), aNeuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosteroneor an analog thereof, a glucocorticoid receptor agonist or antagonist,an orexin receptor antagonist, a urocortin binding protein antagonist, aglucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor(such as Axokine), and human agouti-related protein (AGRP). Otheranti-obesity agents, including the preferred agents set forthhereinbelow, are well known, or will be readily apparent in light of theinstant disclosure, to one of ordinary skill in the art.

Especially preferred anti-obesity agents comprise those compoundsselected from the group consisting of orlistat, sibutramine,fenfluramine, dexfenfluramine, bromocriptine, phentermine, ephedrine,leptin, phenylpropanolamine, and pseudoephedrine.

Representative anti-obesity agents for use in the combinations,pharmaceutical compositions, and methods of the invention can beprepared using methods known to one of ordinary skill in the art, forexample, phentermine can be prepared as described in U.S. Pat. No.2,408,345; sibutramine can be prepared as described in U.S. Pat. No.4,929,629; fenfluramine and dexfenfluramine can be prepared as describedin U.S. Pat. No. 3,198,834; and bromocriptine can be prepared asdescribed in U.S. Pat. Nos. 3,752,814 and 3,752,888; and orlistat can beprepared as described in U.S. Pat. Nos. 5,274,143, 5,420,305, 5,540,917,and 5,643,874.

The present invention further provides methods of treating β₃ adrenergicreceptor-mediated diseases, conditions, or disorders in a mammal in needof such treatment which methods comprise administering to the mammal atherapeutically effective amount of a compound of Formula (I), or astereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the compound, stereoisomer, or prodrug; a combination of a compoundof Formula (I), a stereoisomer or prodrug thereof, or a pharmaceuticallyacceptable salt of the stereoisomer or prodrug and an anti-obesityagent; a pharmaceutical composition comprising an effective amount of acompound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent;or a pharmaceutical composition comprising an effective amount of acompound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent,and an anti-obesity agent.

Preferably, the β₃ adrenergic receptor-mediated disease, condition, ordisorder is selected from the group consisting of obesity, diabetes,irritable bowel syndrome, inflammatory bowel disease, esophagitis,duodenitis, Crohn's Disease, proctitis, asthma, intestinal motilitydisorder, ucler, gastritis, hypercholesterolemia, cardiovasculardisease, urinary incontinence, depression, prostate disease,dyslipidemia, and airway inflammatory disorder.

The invention further provides methods of increasing the lean meatcontent in edible animals which methods comprise administering to theedible animal a lean meat increasing amount of a compound of Formula(I), a stereoisomer, or prodrug thereof, or a pharmaceuticallyacceptable salt of the compound, stereoisomer, or prodrug; apharmaceutical composition comprising a lean meat increasing amount of acompound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent;or a pharmaceutical composition comprising a lean meat increasing amountof a compound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug, and a pharmaceutically acceptable vehicle, carrier, or diluent,and an anti-obesity agent.

The compounds of Formula (I), the stereoisomers and prodrugs thereof,and the pharmaceutically acceptable salts of the compounds,stereoisomers, and prodrugs, can be administered to a patient at dosagelevels in the range of from about 0.01 to about 1,000 mg per day. For anormal adult human having a body weight of about 70 kg, a dosage in therange of from about 0.01 to about 300 mg is typically sufficient.However, some variability in the general dosage range may be requireddepending upon the age and weight of the subject being treated, theintended route of administration, the particular anti-obesity agentbeing administered and the like. The determination of dosage ranges andoptimal dosages for a particular patient is well within the ability ofone of ordinary skill in the art having the benefit of the instantdisclosure. It is also noted that the compounds of the present inventioncan be used in sustained release, controlled release, and delayedrelease formulations, which forms are also well known to one of ordinaryskill in the art.

The dosage of the anti-obesity agent will also be generally dependentupon a number of factors including the health of the subject beingtreated, the extent of treatment desired, the nature and kind ofconcurrent therapy, if any, and the frequency of treatment and thenature of the effect desired. In general, the dosage range of theanti-obesity agent is generally in the range of from about 0.001 toabout 100 mg/kg body weight of the individual per day, preferably fromabout 0.1 to about 10 mg/kg body weight of the individual per day.However, some variability in the general dosage range may also berequired depending upon the age and weight of the subject being treated,the intended route of administration, the particular anti-obesity agentbeing administered and the like. The determination of dosage ranges andoptimal dosages for a particular patient is also well within the abilityof one of ordinary skill in the art having the benefit of the instantdisclosure.

According to the methods of the invention, a compound of Formula (I), astereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the stereoisomer or prodrug; or a compound of Formula (I), astereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the stereoisomer or prodrug and an anti-obesity agent is administeredto a subject in need of treatment therewith, preferably in the form of apharmaceutical composition. In the combination aspect of the invention,the compound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the stereoisomer or prodrug and theanti-obesity agent may be administered either separately or in thepharmaceutical composition comprising both. It is generally preferredthat such administration be oral. However, if the subject being treatedis unable to swallow, or oral administration is otherwise impaired orundesirable, parenteral or transdermal administration will beappropriate.

According to the methods of the invention, when the compound of Formula(I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptablesalt of the stereoisomer or prodrug; or a compound of Formula (I), astereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the stereoisomer or prodrug and an anti-obesity agent areadministered together, such administration can be sequential in time orsimultaneous with the simultaneous method being generally preferred. Forsequential administration, the compound of Formula (I), the stereoisomeror prodrug thereof, or the pharmaceutically acceptable salt of thestereoisomer or prodrug and the anti-obesity agent can be administeredin any order. It is generally preferred that such administration beoral. It is especially preferred that such administration be oral andsimultaneous. When the compound of Formula (I), the stereoisomer orprodrug thereof, or the pharmaceutically acceptable salt of thestereoisomer or prodrug, and the anti-obesity agent are administeredsequentially, the administration of each can be by the same or bydifferent methods.

According to the methods of the invention, the compound of Formula (I),a stereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the stereoisomer or prodrug; or a compound of Formula (I), astereoisomer or prodrug thereof, or a pharmaceutically acceptable saltof the stereoisomer or prodrug and an anti-obesity agent is preferablyadministered in the form of a pharmaceutical composition comprising apharmaceutically acceptable carrier, vehicle, or diluent. Accordingly,the compound of Formula (I), a stereoisomer or prodrug thereof, or apharmaceutically acceptable salt of the compound, stereoisomer, orprodrug; or a compound of Formula (I), a stereoisomer or prodrugthereof, or a pharmaceutically acceptable salt of the stereoisomer orprodrug and an anti-obesity agent can be administered to a patientseparately or together in any conventional oral, rectal, transdermal,parenteral, (for example, intravenous, intramuscular, or subcutaneous)intracisternal, intravaginal, intraperitoneal, intravesical, local (forexample, powder, ointment or drop), or buccal, or nasal, dosage form.

Compositions suitable for parenteral injection may comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Prevention of microorganismcontamination of the compositions can be accomplished with variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride, and the like. Prolonged absorption of injectablepharmaceutical compositions can be brought about by the use of agentscapable of delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, the active compoundis admixed with at least one inert customary pharmaceutical excipient(or carrier) such as sodium citrate or dicalcium phosphate or (a)fillers or extenders, as for example, starches, lactose, sucrose,mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar—agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example, paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite;and/or (i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules and tablets, the dosage forms may alsocomprise buffering agents.

Solid compositions of a similar type may also be used as fillers in softor hard filled gelatin capsules using such excipients as lactose or milksugar, as well as high molecular weight polyethylene glycols, and thelike.

Solid dosage forms such as tablets, dragees, capsules, and granules canbe prepared with coatings and shells, such as enteric coatings andothers well known in the art. They may also contain opacifying agents,and can also be of such composition that they release the activecompound or compounds in a delayed manner. Examples of embeddingcompositions that can be used are polymeric substances and waxes. Theactive compounds can also be in micro-encapsulated form, if appropriate,with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage form may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compound, may further comprisesuspending agents, as for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar—agar, and tragacanth,or mixtures of these substances, and the like.

Compositions for rectal or vaginal administration preferably comprisesuppositories, which can be prepared by mixing a compound of the presentinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax, which are solidat ordinary room temperature, but liquid at body temperature, andtherefore, melt in the rectum or vaginal cavity thereby releasing theactive component.

Dosage forms for topical administration of the compounds of Formula (I),the stereoisomers and prodrugs thereof, and the pharmaceuticallyacceptable salts of the compounds, stereoisomers, and prodrugs; and thecompounds of Formula (I), the stereoisomers and prodrugs thereof, andthe pharmaceutically acceptable salts of the compounds, stereoisomers,and prodrugs and the anti-obesity agents, may comprise ointments,powders, sprays and inhalants. The active agent or agents are admixedunder sterile condition with a pharmaceutically acceptable carrier, andany preservatives, buffers, or propellants that may be required.Opthalmic formulations, eye ointments, powders, and solutions are alsointended to be included within the scope of the present invention.

The following paragraphs describe exemplary formulations, dosages, etc.useful for non-human animals. The administration of the compounds ofFormula (I), the stereoisomers and prodrugs thereof, and thepharmaceutically acceptable salts of the compounds, stereoisomers, andprodrugs; and the compounds of Formula (I), the stereoisomers andprodrugs thereof, and the pharmaceutically acceptable salts of thecompounds, stereoisomers, and prodrugs and the anti-obesity agents, canbe effected orally or non-orally, for example, by injection.

An amount of a compound of Formula (I), or a stereoisomer or prodrugthereof, or a pharmaceutically acceptable salt of the compound,stereoisomer, or prodrug; or a compound of Formula (I), a stereoisomeror prodrug thereof, or a pharmaceutically acceptable salt of thecompound, stereoisomer, or prodrug and an anti-obesity agent, isadministered such that an effective dose is received, generally a dailydose which, when administered orally to an animal is usually betweenabout 0.01 and about 1,000 mg/kg of body weight, preferably betweenabout 0.01 and about 300 mg/kg of body weight.

Conveniently, the compound can be carried in the drinking water so thata therapeutic dosage of the compound is ingested with the daily watersupply. The compound can be directly metered into drinking water,preferably in the form of a liquid, water-soluble concentrate (such asan aqueous solution of a water-soluble salt).

Conveniently, the compound can also be added directly to the feed, assuch, or in the form of an animal feed supplement, also referred to as apremix or concentrate. A premix or concentrate of the compound in acarrier is more commonly employed for the inclusion of the agent in thefeed. Suitable carriers are liquid or solid, as desired, such as water,various meals such as alfalfa meal, soybean meal, cottonseed oil meal,linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal,and mineral mixes such as are commonly employed in poultry feeds. Aparticularly effective carrier is the respective animal feed itself;that is, a small portion of such feed. The carrier facilitates uniformdistribution of the compound in the finished feed with which the premixis blended. It is important that the compound be thoroughly blended intothe premix and, subsequently, the feed. In this respect, the compoundmay be dispersed or dissolved in a suitable oily vehicle such as soybeanoil, corn oil, cottonseed oil, and the like, or in a volatile organicsolvent and then blended with the carrier. It will be appreciated thatthe proportions of compound in the concentrate are capable of widevariation since the amount of active compound in the finished feed maybe adjusted by blending the appropriate proportion of premix with thefeed to obtain a desired level of compound.

High potency concentrates may be blended by the feed manufacturer withproteinaceous carrier such as soybean oil meal and other meals, asdescribed above, to produce concentrated supplements, which are suitablefor direct feeding to animals. In such instances, the animals arepermitted to consume the usual diet. Alternatively, such concentratedsupplements may be added directly to the feed to produce a nutritionallybalanced, finished feed containing a therapeutically effective level ofa compound of the present invention. The mixtures are thoroughly blendedby standard procedures, such as in a twin shell blender, to ensurehomogeneity.

If the supplement is used as a top dressing for the feed, it likewisehelps to ensure uniformity of distribution of the compound across thetop of the dressed feed.

Drinking water and feed effective for increasing lean meat depositionand for improving lean meat to fat ratio are generally prepared bymixing a compound of the invention with a sufficient amount of animalfeed to provide from about 10⁻³ to 500 ppm of the compound in the feedor water.

The preferred medicated swine, cattle, sheep and goat feed generallycontain from 1 to 400 grams of active ingredient per ton of feed, theoptimum amount for these animals usually being about 50 to 300 grams perton of feed.

The preferred poultry and domestic pet feeds usually contain about 1 to400 grams and preferably 10 to 400 grams of active ingredient per ton offeed.

For parenteral administration in animals, the compounds of the presentinvention may be prepared in the form of a paste or a pellet andadministered as an implant, usually under the skin of the head or ear ofthe animal in which increase in lean meat deposition and improvement inlean mean to fat ratio is sought.

In general, parenteral administration involves injection of a sufficientamount of a compound of the present invention to provide the animal with0.01 to 20 mg/kg/day of body weight of the active ingredient. Thepreferred dosage for poultry, swine, cattle, sheep, goats and domesticpets is in the range of from 0.05 to 10 mg/kg/day of body weight ofactive ingredient.

Paste formulations can be prepared by dispersing the active compound ina pharmaceutically acceptable oil such as peanut oil, sesame oil, cornoil or the like.

Pellets containing an effective amount of a compound, pharmaceuticalcomposition, or combination of the present invention can be prepared byadmixing a compound of the present invention with a diluent such ascarbowax, carnuba wax, and the like, and a lubricant, such as magnesiumor calcium stearate, can be added to improve the pelleting process.

It is, of course, recognized that more than one pellet may beadministered to an animal to achieve the desired dose level which willprovide the increase in lean meat deposition and improvement in leanmeat to fat ratio desired. Moreover, it has been found that implants mayalso be made periodically during the animal treatment period in order tomaintain the proper drug level in the animal's body.

The present invention has several advantageous veterinary features. Forthe pet owner or veterinarian who wishes to increase leanness and/ortrim unwanted fat from pet animals, the instant invention provides themeans by which this may be accomplished. For poultry and swine breeders,utilization of the method of the present invention yields leaner animalswhich command higher sale prices from the meat industry.

The terms pharmaceutically acceptable salts, esters, amides, or prodrugsmean the carboxylate salts, amino acid addition salts, esters, amides,and prodrugs of a compound that are, within the scope of sound medicaljudgment, suitable for use with patients without undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible.

The term “salts” refers to inorganic and organic salts of a compound ofFormula (I), or a stereoisomer, or prodrug thereof. These salts can beprepared in situ during the final isolation and purification of acompound, or by separately reacting a compound Formula (I), or astereoisomer or prodrug thereof with a suitable organic or inorganicacid and isolating the salt thus formed. Representative salts includethe hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,oxalate, besylate, palmitiate, stearate, laurate, borate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, andlaurylsulphonate salts, and the like. These may include cations based onthe alkali and alkaline earth metals, such as sodium, lithium,potassium, calcium, magnesium, and the like, as well as non-toxicammonium, quaternary ammonium, and amine cations including, but notlimited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. See, for example, Berge, et al., J. Pharm. Sci., 66, 1-19(1977).

The term “prodrug” means a compound that is transformed in vivo to yielda compound of Formula (I), a stereoisomer thereof, or a pharmaceuticallyacceptable salt of the compound or stereoisomer. The transformation mayoccur by various mechanisms, such as through hydrolysis in blood. Adiscussion of the use of prodrugs is provided by T. Higuchi and W.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

For example, if a compound of Formula (I), a stereoisomer thereof, or apharmaceutically acceptable salt of the compound or stereoisomer,contains a carboxylic acid functional group, a prodrug can comprise anester formed by the replacement of the hydrogen atom of the acid groupwith a group such as (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a compound of Formula (I), or a stereoisomer thereof,comprises an alcohol functional group, a prodrug can be formed by thereplacement of the hydrogen atom of the alcohol group with a group suchas (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a compound of Formula (I), or a stereoisomer thereof, incorporates anamine functional group, a prodrug can be formed by the replacement of ahydrogen atom in the amine group with a group such as R-carbonyl,RO-carbonyl, NRR′-carbonyl where R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OYwherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ wherein Y₀ is (C₁-C₄)alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl ormono-N- or di-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃ wherein Y₂ is H ormethyl and Y₃ is mono-N- or di-N,N-(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond, both the cis- and trans-forms, as well asmixtures, are embraced within the scope of the invention.

Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. Also, some of the compounds of Formula (I) may beatropisomers (e.g., substituted biaryls) and are considered as part ofthis invention.

The compounds of Formula (I) may exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol,and the like, and it is intended that the invention embrace bothsolvated and unsolvated forms.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. For example, all of the tautomeric forms of theimidazole moiety are included in the invention. Also, for example, allketo-enol or imine-enamine forms of the compounds are included in theinvention.

It is also intended that the invention disclosed herein encompasscompounds of Formula (I) that may be synthesized in vitro usinglaboratory techniques, such as those well known to the synthetic organicchemist of ordinary skill, or synthesized using in vivo techniques, suchas through metabolism, fermentation, digestion, and the like. It is alsointended that the compounds of Formula (I) may be synthesized using acombination of in vitro and in vivo techniques.

The present invention also embraces isotopically-labelled compounds ofFormula (I), which are identical to those recited herein, but for thefact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Thecompounds of Formula (I), the stereoisomers and prodrugs thereof, andthe pharmaceutically acceptable salts of the compounds, stereoisomers,or prodrugs which contain the aforementioned isotopes and/or otherisotopes of other atoms are intended to be within the scope of thisinvention.

Certain isotopically-labelled compounds of Formula (I), for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in compound and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by carrying out the procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an isotopically labelled reagent for a non-isotopicallylabelled reagent.

The compounds of Formula (I) may be prepared by processes which includethose known, or those analogous to those known, in the chemical arts.Such processes for the preparation of the compounds of Formula (I) asdefined hereinabove are illustrated according to the exemplary syntheticsequences set forth hereinbelow in Schemes I through Ill. Furthermore,Schemes IV through VI illustrate exemplary synthetic routes to theintermediates useful in the production of the compounds of Formula (I).Unless otherwise qualified, the meanings of the generic radicals are asindicated hereinabove.

In the synthetic sequence designated Scheme I, an appropriatelysubstituted oxirane derivative (III) is condensed with an appropriatelysubstituted amine (II) to produce a compound of Formula (I).

The amine derivatives (II) may be conveniently prepared as depicted ingeneral Schemes IV, V, and VI hereinbelow, however, other methods ofpreparing such amine derivatives will be known to one of ordinary skillin the art having benefit of the teachings of the instant disclosure.

The oxirane derivatives (III) may be prepared according to knownmethods, including those set forth in, for example, U.S. Pat. Nos.5,541,197, 5,561,142, 5,705,515, and 6,037,362, the disclosures of whichare all incorporated herein by reference. Where available, such oxiranederivates may also be obtained from commercial sources.

The condensation of oxirane (III) and amine (II) is most convenientlyperformed at an elevated temperature in a polar, protic solvent, forexample, an alcohol such as methanol or ethanol. Alternatively, aco-solvent system may also be employed, for example, by adding a polar,aprotic co-solvent such as dimethylsulfoxide to the protic solvent.Isolation and purification of the compound of Formula (I) thus formedmay then be effected according to known methods. An example of suchcondensation and purification is disclosed hereinbelow in the generalpreparative method denoted Method A.

Alternatively, as depicted in Scheme II, the compounds of Formula (I)may also be prepared by condensing an appropriately substitutedprotected alcohol (IV) with an amine (II). The protected alcohol (IV)incorporates a suitable leaving group that is susceptible todisplacement by nucleophilic attack of the nitrogen atom of amine (II).Suitable leaving groups that may be employed in protected alcohol (IV)may comprise, for example, mesylates, tosylates, and nosylates, orhalides, for example, chlorides, bromides, or iodides. The protectedalcohol derivatives (IV) may be prepared according to known methods,including, for example, those methods disclosed in commonly-assignedU.S. Pat. No. 6,008,361, the disclosure of which is hereby incorporatedby reference. However, other methods of preparing such protectedalcohols will be known, or apparent in light of the instant disclosure,to one of ordinary skill in the art. See, for example, T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,(1991), and the references cited therein.

The condensation of protected alcohol (IV) and amine (II) is typicallyeffected in the presence of an appropriate, sterically-hindered base,for example, N,N-diisopropylethylamine (Hunig's Base) in a polar,aprotic solvent, such as dimethylsulfoxide, at elevated termperature.The protected amino alcohol (V) thus formed may then be deprotectedaccording to well-known preparative methods, for example, where (V) is asilylated derivative, preferably by treatment with tetrabutylammoniumfluoride. An example of such condensation and deprotection is disclosedhereinbelow in the general preparative method denoted as Method B.

Alternatively, as shown in Scheme III, the compounds of Formula (I) mayalso be prepared by dehalogenation of a compound of Formula (Ia),wherein the Ar group represents an appropriately substituted6-chloropyridine derivative.

The dehalogenation of the above-mentioned 6-chloropyridine derivative(Ia) may be effected according to known methods. Most conveniently, suchdehalogenation is performed using a metal catalyst, preferably palladiumon carbon, in a polar solvent, such as methanol. The reaction ispreferably conducted at room temperature over a period of several hours,i.e. overnight. Other methods of effecting dehalogenation reactions ofthis kind will be known to one of ordinary skill in the art. An exampleof such dehalogenation reaction is disclosed hereinbelow in the generalpreparative method denoted Method C.

With reference to Schemes I and II, the aforementioned amine derivativesof formula (II) may be prepared according to the exemplary syntheticsequences depicted hereinbelow in Schemes IV, V, and VI. It is to beunderstood, however, that such examples are offered for purposes ofillustration of these embodiments of the instant invention and are notto be construed in any manner as limitations thereof, as other methodsof preparing such amine derivatives will be known, or apparent, to oneof ordinary skill in the art having benefit of the instant disclosure.

General Scheme IV hereinabove depicts a convenient, exemplary syntheticroute to amine derivatives (II) in which an appropriately substitutedanisole derivative (VI) serves as the synthetic platform upon which theheterocyclic moiety R₅ may be constructed. Such anisole derivatives willbe well known to one of ordinary skill in the art and may either beprepared according to known methods or obtained commercially. Theanisole derivatives (VI) may be functionalized as illustratedhereinbelow in Schemes IVa to IVc to produce heteroaryl derivatives(VII). Although general Scheme IV, and the synthetic schemes relatedthereto that are shown below, depict the use of an anisole derivative(VI), it is to be understood that an appropriately substituted phenolderivative may also be employed in place of the anisole derivative,where such phenol is chemically compatible with other functional groupsand/or reagents that may be present or utilized in subsequent syntheticsteps. The heteroaryl derivatives (VIII) so produced are thendemethylated, for example, with methanesulfonic acid or borontribromide, to form an appropriately substituted phenol derivative(VIII). The phenol derivative (VIII) so produced is then coupled with aprotected amino alcohol to form the amine-protected derivative (IX). Anexample of such coupling reaction is provided hereinbelow in Example 1.The ability to select an appropriate amine-protecting group to form theamine-protected alcohol (IX) is well within the purview of one ofordinary skill in the art. For examples of typical amine protectinggroups, see, for example, T. W. Greene, supra, and the references citedtherein. The coupling reaction between the phenol derivative (VIII) andthe amine-protected derivative (IX) may be effected according tomethodologies that will be well-known to one of ordinary skill in theart, however, such coupling is preferably effected via a so-calledMitsunobu reaction. This reaction is typically performed with stirringat room temperature (or at elevated temperature if required) in thepresence of a dehydrating agent, for example, a stoichiometric amount ofa diazocarboxyl compound, such as 1,1′-(azodicarbonyl)-dipiperidine(ADDP), and a phosphine, for example, triphenylphosphine. The reactioncan be carried out in any reaction-inert solvent such astetrahydrofuran, dimethylformamide, or a hydrocarbon, or halogenatedhydrocarbon solvent. The amine-protected derivative (IX) so formed isthen deprotected in a conventional manner, for example, by treatmentwith methanesulfonic acid, or various other deprotecting agents underconditions that will be well known to one of ordinary skill in the art,including hydrogenoloysis in the presence of a suitable metal catalyst,such as palladium on carbon in an inert solvent. The hydrogenolysisreaction is typically effected anywhere from room temperature up toabout 90° C. An example of such a deprotection reaction is providedhereinbelow in Example 2.

The following specific schemes, designated Schemes IVa to IVe, exemplifythe syntheses of various synthetic precursors to the various aminederivatives (II) depicted in Schemes I, II, and IV wherein theheterocyclic moiety R₅ is as shown hereinbelow. As before, it is to beunderstood that these examples are offered for purposes of illustration,and not of limitation.

The thiazole, oxazole, and imidazole-functionalized anisole derivatives(VIIa) may be produced according to the exemplary route depicted inScheme IVa, beginning with an appropriately substituted thioamide,amide, or amidine derivative (VIa). Such thioamide, amide, or amidinederivatives will be well known to one of ordinary skill in the art andmay either be obtained commercially or prepared by known preparativemethods. The thioamide, amide, or amidine derivative (VIa) is cyclizedwith an appropriate α-bromoketone to form the desired derivative (VIIa).Such α-bromoketones will also be well known to one skilled in the artand may also be obtained commercially or prepared by one of ordinaryskill in the art according to known methods.

Alternatively, regioisomeric thiazole, oxazole, and imidazolederivatives (VIIb) can be synthesized according to the exemplarysynthetic route shown in Scheme IVb. In Scheme IVb, an appropriatelysubstituted acylated anisole derivative (VIb) is α-halogenated,preferably α-brominated, according to conventional methods, for example,by the reaction of (VIb) with tetrabutylammonium tribromide (TBABBr₃),or dibromobarbituric acid (DBBA). The substituted α-bromoketone (VIb′)so produced is then condensed with an appropriate thioamide, amide, oramidine derivative to form the thiazole, oxazole, or imidazolederivative (VIIb). Such condensation may be effected neat, or,preferably, in the presence of a polar solvent, such as an alcohol, or ahalogenated hydrocarbon, such as chloroform.

The intermediate isoxazole or pyrazole derivatives (VIIc) may besynthesized according to the exemplary route depicted in Scheme IVc. InScheme IVc, an acylated anisole derivative (VIc) is reacted with anappropriately substituted ester and a crown ether, for example,18-crown-6, in the presence of an organic base, such as potassiumtert-butoxide, in a non-protic solvent, such as tetrahydrofuran, atelevated temperature. The diketo derivative (VIc′) thus formed is thencyclized with an appropriately substituted hydrazine derivative orhydroxylamine in a polar solvent, such as ethanol, at elevatedtemperature to produce pyrazole derivative (VIIc), and the regioisomerthereof (VIIc′).

The intermediate isoxazole or pyrazole derivatives (VIId) may besynthesized according to the exemplary route depicted in Scheme IVd. InScheme IVd, an appropriately substituted diketo derivative (IVd) iscondensed with an appropriately substituted hydrazine derivative orhydroxylamine to furnish phenol derivatives (VIId). The intermediatediketo derivative (VId) may be obtained from commercial sources orprepared according to known methods. The condensation reaction ispreferably effected in a polar solvent, such as ethanol, at elevatedtemperature. An exemplary preparation of a compound of formula (VIIId)is provided in Example 35 hereinbelow.

The intermediate imidazole derivatives (VIIe) or pyrazole derivatives(VIIe′) may be prepared as outlined hereinabove in exemplary Scheme(IVe). As depicted in Scheme (IVe), an appropriately substituted boronicacid derivative (VIe) is reacted with an appropriately substitutedimidazole or pyrazole derivative in the presence of a suitable catalyst,preferably copper (II) acetate, in a halogenated hydrocarbon solvent,preferably dichloromethane, to form imidazole derivative (VIIe) orpyrazole derivative (VIIe′) respectively. The boronic acid derivatives(VIe), as well as the appropriately substituted imidazole or pyrazolederivatives, may be either obtained commercially or prepared accordingto known methods. An exemplary preparation of a compound of formula(VIIe′) is provided in Example 30 hereinbelow.

Scheme V hereinabove depicts an exemplary, alternative route to aformula (II) amine beginning with an appropriately substitutedfluorobenzene derivative (X). Such fluorobenzene derivatives (X) may beobtained commercially, or, in the alternative, may be prepared by knownmethods. The fluorobenzene derivative (X), which serves as a syntheticscaffold from which the heterocyclic moiety R₅ is assembled, is reactedwith an appropriately functionalized amino alcohol to furnish amine(II). The reaction between the amino alcohol and the fluorobenzenederivative (XI) is typically effected in a polar, aprotic solvent,preferably dimethylsulfoxide, at an elevated temperature in the presenceof an organic or inorganic base, preferably potassium tert-butoxide. Arepresentative synthesis of an amine (II) as depicted in Scheme V isprovided hereinbelow in Examples 28 and 29.

Scheme Va above illustrates a convenient, generally applicable syntheticapproach to the heterocyclic amine precursor of formula (XI) shown inScheme V, wherein R₅ represents a pyridazin-3-one moiety. Here, thefluorobenzene starting material (Xa) is condensed with hydrazine hydratein a polar, protic solvent, such as ethanol, at elevated temperature, toform amine precursor (XIa). An exemplary synthesis of precursor (XIa) asshown in Scheme Va is disclosed hereinbelow in Example 28.

A generally applicable, alternative synthesis of an amine intermediate(II) is shown in Scheme VI beginning with protected amine (XII). Theprotected amine (XII), which may be prepared by known methods, isfunctionalized so as to form amine (IX) which subsequently serves as asynthetic basis for the preparation of protected amine (IX) whichincorporates the substituted heterocyclic moiety R₅. Representativepreparations of such heterocyclic moieties are illustrated hereinbelowin Schemes VIa to VId. Typically, the protected amine starting material(XII), wherein X is a direct bond, is prepared by appropriatederivatization of a commercially available phenalkylamine startingmaterial. An example of such derivatization is disclosed hereinbelow inExample 11. Where X represents oxygen, such protected amine derivatives(XII) are typically derived from an aforementioned Mitsunobu couplingreaction between an appropriately substituted, commercially availablephenol and an ethanolamine derivative. An example of such a couplingreaction is provided hereinbelow in Example 20.

In Scheme VIa, the amine-protected derivative (XIIa) is acylated understandard Friedel-Crafts reaction conditions to form the acyl derivative(XIIa′). Such acylation will be well known to one of ordinary skill inthe art and is typically effected by treating (XIIa) with anappropriately substituted acyl chloride in the presence of a Lewis acid,i.e. aluminum (III) chloride in a reaction-inert solvent, such asdichloromethane or similar halogenated hydrocarbon solvent at, or below,room temperature. The acylated derivate (XIIa) so produced is thenα-halogenated relative to the keto group of the acyl moiety to formα-haloketone (XIIa″). Such α-halogenation, preferably α-bromination, maybe effected according to conventional methods, preferably by thereaction of (XIIa) with tetrabutylammonium tribromide (TBABBr₃), ordibromobarbituric acid (DBBA). An example of such an α-brominationreaction is provided hereinbelow in Example 21. The preferredα-bromoketone (XIIa″) so produced is then condensed with an appropriatethioamide, amide, or amidine derivative to form a protected thiazole,oxazole, or imidazole derivative (IXa) respectively. Although thecondensation reaction may be effected in the absence of a solvent, i.e.neat, for purposes of product purity and ease in reaction work-up andpurification, it is generally preferred that the condensation reactionbe performed in a reaction-inert solvent, including, for example,ethanol, chloroform, or similar solvent. An example of such condensationreaction is provided in Example 22 hereinbelow. The protected aminederivative (IXa) so produced may then be deprotected according to themethodologies described hereinabove in Scheme IV. An example of suchdeprotection reaction is provided hereinbelow in Example 23.

The protected triazole derivatives (IXb) shown in Scheme VIb may beproduced by reaction of an amine-protected amide derivative (XIIb) withan appropriately substituted dimethylaminodimethylacetal at elevatedtemperature under neat conditions followed by treatment with hydrazinehydrate in glacial acetic acid, also at elevated temperature. Theprotected amine derivative (IXb) thus formed may then be deprotected asshown and described hereinabove in Scheme IV.

The oxadiazole derivatives (IXc) shown in Scheme VIc may be synthesizedby reacting an appropriately substituted hydrazide (XIIc) with an acylchloride under standard conditions, i.e., in the presence of a base,preferably an organic base such as triethylamine, in a reaction-inertsolvent such as dichloromethane. If necessary, the resulting diacylhydrazide intermediate may then be treated with a cyclizing agent, suchas triflic anhydride, to effect ring closure. The protected aminederivative (IXc) thus produced may then be deprotected as shown anddescribed hereinabove in Scheme IV. An exemplary synthetic sequence,which illustrates the preparation of a protected amine derivative (IXc),as well as the subsequent deprotection thereof, is provided in Examples24 to 27 hereinbelow, wherein Y represents —CH₂—.

The protected thiazole, oxazole, or imidazole derivates (IXd) depictedin Scheme VId may be prepared beginning with nitrile (XIId). Typically,nitrile (XIId) is prepared via the aforementioned Mitsunobu couplingreaction between commercially available phenol and ethanolaminederivatives. Reduction of nitrile (XIId) with, for example, a metalhydride such as diisobutylaluminum hydride (DIBAL-H) in areaction-inert, hydrocarbon solvent such as toluene or hexanes, or ahalogenated hydrocarbon solvent such as dichloromethane furnishesaldehyde (XIId′). The aldehyde (XIId′) so produced is then α-halogenatedto form α-haloaldehyde (XIId″). Such α-halogenation is preferablyeffected as set forth hereinabove in Scheme VIa. The preferredα-bromoaldehyde (XIIa″) is then condensed with an appropriate thioamide,amide, or amidine derivative to form the protected thiazole, oxazole, orimidazole derivative (IXd), preferably also according to the methoddisclosed hereinabove in Scheme VIa. The protected amine derivative(IXd) so formed may then be deprotected as shown and describedhereinabove in Scheme IV.

Conventional methods and/or techniques of separation and purificationknown to one of ordinary skill in the art can be used to isolate thecompounds of Formula (I), as well as the various intermediates relatedthereto. Such techniques will be well-known to one of ordinary skill inthe art and may include, for example, all types of chromatography (HPLC,column chromatography using common adsorbents such as silica gel, andthin-layer chromatography), recrystallization, and differential (i.e.,liquid—liquid) extraction techniques.

EXPERIMENTAL

Chemical Syntheses

The embodiments of the present invention are illustrated by thefollowing Examples. It is to be understood, however, that theembodiments of the invention are not limited to the specific details ofthese Examples, as other variations thereof will be known, or apparentin light of the instant disclosure, to one of ordinary skill in the art.

Example 1

{2-[4-(4-Methyl-oxazol-2-yl)-phenoxyl-ethyl}-Carbamic Acid Benzyl Ester

[2-(4-Carbamoyl-phenoxy)-ethyl]-carbamic acid benzyl ester (322 mg, 1.02mmol) and 1-bromo-2,2-dimethoxypropane (3.8 g, 20.4 mmol) were combinedin a round-bottomed flask and heated to about 130° C. for about thirtyminutes. The reaction mixture was then cooled to room temperature andpoured into water. The mixture was extracted with ethyl acetate, thecombined extracts dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting crude material was purified bycolumn chromatography (1:1 hexanes/ethyl acetate) to afford the desiredoxazole product (167 mg, 47% yield). LRMS ([M+H]⁺)=353.1.

Example 2

2-[4-(4-Methyl-oxazol-2-yl)-phenoxyl-ethylamine

The title compound of Example 1,{2-[4-(4-Methyl-oxazol-2-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester,(166 mg, 0.47 mmol) was dissolved in methanol (5 ml) and 10% Pd/C (50mg) and 1,4-cyclohexadiene (192 mg, 2.4 mmol) were added to theresulting solution. The mixture was allowed to stir for about sixteenhours, and then it was filtered through diatomaceous earth, and thefilter pad was washed with methanol. The filtrate was concentrated invacuo to dryness, and the resulting material (92 mg, 90% yield), whichwas determined to be pure by ¹H NMR, was used directly without furtherpurification. LRMS ([M+H]⁺)=219.2.

Example 3

4-Hydroxy-thiobenzamide

In a round bottomed flask, 4-hydroxybenzonitrile (5.00 g, 41.9 mmol),diethylthiophosphoric acid (7.02 g, 41.9 mmol), and water (8 ml) wereheated with stirring to about 80° C. for about thirty minutes. Anadditional 10 ml of water was then added to the suspension, and thereaction was heated for about another one hour. The mixture was thenallowed to stir for about sixteen hours at room temperature and was thenextracted with water and 1:1 ether/ethyl acetate. The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo. The resulting solid was purified by column chromatography(silica gel; hexanes to ethyl acetate). The product was isolated as ayellow solid (5.54 g, 87% yield). ¹H NMR (CD₃OD): δ6.74 (d, 2H, J=9.1Hz), 7.83 (d, 2H, J=8.7 Hz).

Example 4

4-(4-Phenyl-thiazol-2-yl)-phenol

In a round-bottomed flask, 2-bromoacetophenone (520 mg, 2.61 mmol) and4-hydroxy-thiobenzamide (400 mg, 2.61 mmol) were dissolved in ethanol(10 ml), and the resulting solution was heated to reflux. After aboutone hour, the reaction was cooled to about 35° C. and was allowed tostir for about an additional twelve hours. The reaction mixture was thenconcentrated in vacuo to an oil, the residue redissolved in ethylacetate and methylene chloride, and extracted with saturated aqueoussodium bicarbonate. The combined extracts were then extracted withbrine, dried over magnesium sulfate, filtered, and concentrated in vacuoto an oil. The crude product was purified by column chromatography(silica gel; methylene chloride to 2% methanol/methylene chloride). Thetitle product was isolated as a white solid (516 mg, 78% yield). LRMS([M+H]⁺)=254.1.

Example 5

Benzyl-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxyl-ethyl}-carbamate

4-(4-Phenyl-thiazol-2-yl)-phenol (516 mg, 2.03 mmol) was dissolved intoluene (6.8 ml), and triphenylphosphine (786 mg, 3.00 mmol) and benzylN-(2-hydroxyethyl)-carbamate (585 mg, 3.00 mmol) were added. Thesolution was cooled to about 0° C. and 1,1-(azodicarbonyl)-dipiperidine(757 mg, 3.00 mmol) was added. The mixture was allowed to stir for about10 minutes at about 0° C. and was then allowed to warm to roomtemperature. An additional 6.8 ml of toluene and 6.8 ml oftetrahydrofuran were added to the viscous solution. The reaction mixturewas stirred for about forty-eight hours, and then the solids werefiltered off and rinsed with a minimum volume of 1:1toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to asemisolid which was then purified by column chromatography (silica gel;methylene chloride to 2% methanol/methylene chloride) to give 396 mg ofpure product (45% yield). LRMS ([M+H]⁺)=430.9.

Example 6

2-[4-(4-Phenyl-thiazol-2-yl)-phenoxyl-ethylamine

Benzyl-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethyl}-carbamate (396 mg,0.92 mmol) was dissolved in methylene chloride (4.6 ml) andmethanesulfonic acid (0.895 ml, 13.8 mmol) was added dropwise to give ahomogenous yellow solution. The reaction mixture was allowed to stir forabout sixteen hours, diluted with methylene chloride, and was brought tobasic pH (12-13) with 1M sodium hydroxide. The mixture was thenextracted with methylene chloride, and the combined organic extractswere dried over magnesium sulfate, filtered, and concentrated in vacuo.The resulting crude material was purified by column chromatography(silica gel; methylene chloride to 2% methanol/methylene chloride) toafford the product in 78% yield (213 mg). LRMS ([M+H]⁺)=297.2.

Example 7

Benzyl-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxyl-ethyl}-carbamate

Acetamidine hydrochloride (112 mg, 1.18 mmol),benzyl-[2-(4-bromoacetyl-phenoxy)-ethyl]-carbamate (160 mg, 0.39 mmol),and sodium ethoxide (80.3 mg, 1.18 mmol) were combined in around-bottomed flask, dissolved in ethanol, and heated to about 80° C.for about two hours. The reaction mixture was then allowed to cool toroom temperature, and the resulting heterogenous mixture was filtered.The filtrate was then concentrated in vacuo to an oil which was purifiedby column chromatography (silica gel; 5% methanol/methylene chloride to10% methanol/methylene chloride) to afford 92 mg (64% yield) of thedesired product. LRMS ([M+H]⁺)=352.2.

Example 8

2-[4-(2-Methyl-1H-imidazol-4-yl)-phenoxyl-ethylamine

In a nitrogen-purged Parr flask,benzyl-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethyl}-carbamate (78mg, 0.22 mmol) was dissolved in methanol (15 ml), and 10% Pd/C (20 mg)was added in one portion. The material was then hydrogenated at about 45psi for about four hours. The reaction mixture was then filtered througha pad of diatomaceous earth and the filter pad was washed with methanol.The filtrate was concentrated in vacuo, and the resulting material (49mg, 100% yield) was carried on without further purification. LRMS([M+H]⁺)=218.2.

Example 9

N-[2-(4-Acetyl-phenyl)-ethyl]-acetamide

In a 500 ml flame-dried flask, N-phenethyl-acetamide (6.53 g, 40.0 mmol)was dissolved in methylene chloride (65 ml), and acetyl chloride (7.22g, 92.0 mmol) was added in one portion. The resulting solution wascooled to about 0° C., and aluminum chloride (18.1 g, 136 mmol) wasadded in portions over about thirty minutes. The solution was stirredfor about five minutes at about 0° C., and the ice bath was then removedand the mixture was heated to reflux for about thirty minutes. Aftercooling to room temperature, the reaction mixture was poured over icewater, stirred for about ten minutes, and then extracted with methylenechloride (2×100 ml). The combined organic extracts were then washedsequentially with water and brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting white solid (7.52 g,92% yield) was ascertained to be about 90% pure by NMR, and was employeddirectly without further purification. LRMS ([M+H]⁺)=206.2.

Example 10

N-[2-(4-Bromoacetyl-phenyl)-ethyl]-acetamide

In a round-bottomed flask, N-[2-(4-acetyl-phenyl)-ethyl]-acetamide (7.23g, 35.2 mmol) was dissolved in methylene chloride (120 ml), and methanol(60 ml). Tetrabutylammonium tribromide (17.0 g, 35.2 mmol) was added tothis solution in one portion, and the mixture was allowed to stirovernight at room temperature. The volatiles were then removed in vacuoto afford an oil, which was then resuspended in 100 ml of methylenechloride and extracted with 125 ml of saturated aqueous sodiumbicarbonate. The aqueous extracts were reextracted with methylenechloride (3×100 ml), and the combined organic extracts were then washedwith water, dried over magnesium sulfate, filtered, and concentrated invacuo. The crude oil was purified by column chromatography (silica gel;methylene chloride to 7% methanol/methylene chloride), and the resultingmaterial was washed with 110 ml of water to afford 8.27 g (83% yield) ofpure product as a white solid. LRMS ([M−1 ]⁻)=283.0, 284.9.

Example 11

N-[2-[4-(2-Phenyl-thiazol-4-yl)-phenyl]-ethyl}-acetamide

In a round-bottomed flask, thiobenzamide (357 mg, 2.60 mmol) andN-[2-(4-bromoacetyl-phenyl)-ethyl]-acetamide (740 mg, 2.60 mmol) werecombined in ethanol (30 ml) and heated to about 80° C. for about threehours. The reaction mixture was then concentrated in vacuo to yield anoff-white solid. The resulting material (838 mg, 100% yield) wasascertained to be pure by NMR and was carried into the next stepdirectly without further purification. LRMS ([M+H]⁺)=323.2.

Example 12

2-[4-(2-Phenyl-thiazol-4-yl)-phenyl]-ethylamine

In a round-bottomed flask,N-{2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethyl}-acetamide (838 mg, 2.60mmol) was added to 5.0 ml of concentrated HCl and the resulting solutionwas heated to about 120° C. for about sixteen hours. The solution wasthen cooled to about 0° C., brought to pH 12 with 5M sodium hydroxide,and extracted with four portions of methylene chloride. The combinedorganic extracts were then washed with brine, dried over magnesiumsulfate, and concentrated in vacua. The crude material was purified bycolumn chromatography (silica gel; methylene chloride to 20%methanol/methylene chloride) to afford the product (617 mg, 85% yield).LRMS ([M+H]⁺)=281.2.

Example 13

N-(1,1-Dimethyl-2-phenyl-ethyl)-2,2,2--trifluoroacetamide

In a 500 ml flame-dried flask, phentermine hydrochloride (5.0 g, 26.9mmol) and pyridine (7.0 ml, 86.2 mmol) were dissolved in methylenechloride (100 ml). The resulting solution was cooled to about 0° C., andtrifluoroacetic anhydride (7.6 ml, 53.9 mmol) was added dropwise overabout four minutes. The solution was stirred for about five minutes atabout 0° C., and the ice bath was then removed. After stirring for aboutninety minutes at room temperature, the reaction mixture was recooled toabout 0° C. and 100 ml of saturated aqueous ammonium chloride was added.The organic and aqueous layers were then separated, and the aqueouslayer was reextracted with another 100 ml portion of methylene chloride.The combined organic extracts were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingwhite solid (6.35 g, 96% yield) was used without further purification.LRMS ([M−1]⁻)=244.2.

Example 14

N-[2-(4-Acetyl-phenyl)-1,1-dimethyl-ethyl]-2,2,2-trifluoroacetamide

A flame-dried 250 ml flask was charged withN-(1,1-dimethyl-2-phenyl-ethyl)-2,2,2-trifluoroacetamide (5.93 g, 24.2mmol), acetyl chloride (4.00 g, 55.6 mmol), and methylene chloride. Theresulting solution was cooled to about 0° C., and aluminum (III)chloride (11.0 g, 82.2 mmol) was added in portions over about thirtyminutes. Over the course of the addition, the solution changed fromcolorless to greenish-brown. After the addition was complete, thesolution was heated to reflux for about thirty minutes, and was thencooled to room temperature and poured over 300 ml of ice water. Afterstirring for about ten minutes, the mixture was diluted with 125 ml ofmethylene chloride, and the layers were separated. The aqueous layer wasextracted with an additional 125 ml of methylene chloride. The combinedorganic extracts were then washed with water and brine, sequentially,and then dried over magnesium sulfate, filtered, and concentrated invacuo. The resulting oil, (6.9 g, 99% yield) which was ascertained to beabout 85% pure by NMR, was carried into the subsequent reaction withoutfurther purification. LRMS ([M+1]⁺)=288.2.

Example 15

N-[2-(Bromoacetyl-phenyl)-1,1-dimethyl-ethyl]-2,2,2-trifluoroacetamide

In a round-bottomed flask,N-(1,1-dimethyl-2-phenyl-ethyl)-2,2,2-trifluoroacetamide (6.90 g, 21.0mmol) was dissolved in methylene chloride (66 ml) and methanol (33 ml).Tetrabutylammonium tribromide (10.6 g, 22.0 mmol) was added to thissolution in one portion, and the mixture was allowed to stir at roomtemperature overnight. The volatiles were then removed in vacuo to anoil, which was then resuspended in 100 ml of methylene chloride andextracted with 125 ml of saturated aqueous sodium bicarbonate. Theaqueous extracts were reextracted with methylene chloride (3×10 ml), andthe combined organic extracts were then washed with water and dried overmagnesium sulfate, filtered, and concentrated in vacuo. The crude oilwas purified by column chromatography (silica gel; 60% methylenechloride/hexanes to 10% ethyl acetate/methylene chloride), and theresulting material (5.18 g) was recrystallized from hexanes to afford3.14 g (41% yield) of pure product as a fluffy white solid.

Example 16

N-{1,1-Dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethyl}-2,2,2-trifluoroacetamide

In a round-bottomed flask,N-[2-(bromoacetyl-phenyl)-1,1-dimethyl-ethyl]-2,2,2-trifluoroacetamide(388 mg, 1.06 mmol) and thioacetamide (80 mg, 1.06 mmol) were dissolvedin ethanol (10 ml), and the mixture was heated to about 80° C. for abouttwo and one-half hours. The reaction mixture was then concentrated invacuo to an oil which was carried into the next reaction without furtherpurification. LRMS ([M+1]⁺)=343.2.

Example 17

1,1-Dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamine

In a round-bottomed flask,N-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethyl}-2,2,2-trifluoroacetamide(˜362 mg, 1.06 mmol) was suspended in 7.5 ml of 2:1 (v:v)methanol/tetrahydrofuran, and 5M sodium hydroxide (3.2 ml, 15 equiv.)was added dropwise. The solution turned from colorless to golden brown,and was then allowed to stir at room temperature overnight. The reactionmixture was then concentrated in vacuo to remove volatiles, and theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The aqeuous layer was removed and was washed twicemore with ethyl acetate. The combined organic extracts were then washedwith brine, dried over magnesium sulfate, filtered, and concentrated invacuo to afford the product (242 mg, 93% yield for both steps), whichwas used directly without further purification. LRMS ([M+1]⁺)=247.3.

Example 18

tert-Butyl-{2-[4-(5-methyl-4H-[1,2,4]-triazol-3-ylmethyl)-phenoxyl-ethyl}-carbamate

tert-Butyl-[2-(4-carbamoylmethyl-phenoxy)-ethyl]-carbamate (605 mg, 2.05mmol) and N,N-dimethylacetamide dimethylacetal (5 ml) were combined andheated to about 120° C. for about ninety minutes. The orange solutionwas then allowed to cool to room temperature and was concentrated invacuo. The resulting oil was then dissolved in acetic acid (6 ml), andhydrazine hydrate (0.20 ml, 4.10 mmol) was added to the solution. Themixture was heated to about 90° C. for about ninety minutes and was thenpoured into water and brought to pH 7 by adding 5M sodium hydroxide. Thematerial was then partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate, and extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude material waspurified by column chromatography (silica gel; chloroform to 4%methanol/chloroform) to afford 403 mg (59% yield) of the desiredproduct. LRMS ([M+H]⁺)=333.2.

Example 19

2-[4-(5-Methyl-4H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethylamine

To a solution oftert-butyl-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethyl}-carbamate(380 mg, 1.14 mmol) in methylene chloride (10 ml) was addedtrifluoroacetic acid (1.7 ml). The resulting mixture was stirred forabout thirty minutes and was then concentrated in vacuo. The resultingcrude oil was then dissolved in ethyl acetate and brought to pH 10 withaqueous sodium hydroxide. The aqueous layer was extracted with ethylacetate, and the combined organic extracts were washed with brine, driedover magnesium sulfate, filtered, and concentrated in vacuo to afford120 mg (45% yield) of the amine product. LRMS ([M+H]⁺)=233.1.

Example 20

Benzyl-[2-(4-acetyl-phenoxy)-ethyl]-carbamate

In around-bottomed flask equipped with a mechanical stirrer,4-hydroxyacetophenone (5.00 g, 36.7 mmol) was dissolved in toluene (122ml), and triphenylphosphine (14.4 g, 55.1 mmol), and benzylN-(2-hydroxyethyl)carbamate (10.8 g, 55.1 mmol) were added. The reactionmixture was cooled to about 0° C., and 1,1′-(azodicarbonyl)dipiperidine(13.9 g, 55.1 mmol) was added in one portion. The mixture was allowed towarm to room temperature, and after stirring for about ten minutes, anadditional 122 ml of toluene and 122 ml of tetrahydrofuran were added tothe thick orange solution. The mixture was stirred for an additionaltwenty-four hours, and the solids were filtered off. The filtrate wasconcentrated in vacuo and the resulting solid was purified by columnchromatography (silica gel; hexanes to 2:1 hexanes/ethyl acetate) toafford 9.68 g (84% yield) of the desired product as a white solid. LRMS([M−1]⁻)=312.2.

Example 21

Benzyl-[2-(4-bromoacetylphenoxy)-ethyl]-carbamate

Benzyl-[2-(4-acetyl-phenoxy)-ethyl]-carbamate (10.2 g, 32.5 mmol) wasdissolved in methylene chloride (100 ml) and methanol (50 ml), andtetrabutylamonium tribromide (15.7 g, 32.5 mmol) was added in oneportion. The reaction mixture was stirred for about sixteen hours, andthen quenched with water. The aqueous phase was extracted with ethylacetate and then washed with saturated aqeous sodium bicarbonate, andsaturated Na₂S₂O₃. The combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated in vacuo, and theresulting crude material was purified by column chromatography (silicagel; hexanes to 2:1 hexanes/ethyl acetate) to afford a colorless oilwhich solidified upon standing. (11.5 g, 90% yield).

Example 22

Benzyl-[2-[4-(2-methyl-oxazol-4-yl)-phenoxyl-ethyl]-carbamate

Acetamide (2.95 g, 50.0 mmol) andbenzyl-[2-(4-bromoacetylphenoxy)-ethyl]-carbamate (1.20 g, 3.06 mmol)were combined in a round-bottomed flask and heated to about 130° C. forabout ninety minutes. The reaction mixture was then allowed to cool toroom temperature, and the resulting orange solid was partitioned betweenethyl acetate and water and extracted three times with ethyl acetate.The combined organic extracts were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingcrude solid was purified by column chromatography (silica gel; methylenechloride to 10% ethyl acetate/methylene chloride) to afford 621 mg (58%yield) of the product as a white solid. LRMS ([M+H]⁺)=353.3.

Example 23

2-[4-(2-Methyl-oxazol-4-yl)-phenoxyl-ethylamine

A round-bottomed flask containingbenzyl-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethyl}-carbamate (788 mg,2.07 mmol) was purged with nitrogen, and 10% Pd/C (200 mg, 20 wt %),ethyl acetate (15 ml), and methanol (5 ml) were added.1,4-cyclohexadiene (0.90 ml, 9.60 mmol) was then added to the mixture,and the solution was allowed to stir at room temperature for about onehour. The reaction mixture was then filtered through a pad ofdiatomaceous earth and the filter cake was washed with methanol. Thefiltrate was concentrated in vacuo and the residue purified by columnchromatography (silica gel; methylene chloride to 20% methanol/methylenechloride) to afford 456 mg (89% yield) of the desired product. LRMS([M+H]⁺)=247.2.

Example 24

Imidodicarbonic Acid,[2-[4-[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-oxoethyl]phenoxy]ethyl]-,bis(1,1-dimethylethyl)ester

In a round-bottomed flask,2-[4-(2-amino-ethoxy)-phenyl]-N-methyl-acetamide (7.78 g, 37.3 mmol) wasdissolved in dimethylsulfoxide (30 ml), and di-tert-butyl dicarbonate(12.2 g, 55.9 mmol) was added in one portion at room temperature. Afterthe reaction was stirred for about ninety minutes, dimethylaminopyridine(4.56 g, 37.3 mmol) and an additional 8.14 g (37.3 mmol) ofdi-tert-butyl dicarbonate were added. After a total of about four hours,an additional portion of dimethylaminopyridine (12.2 g, 55.9 mmol) wasadded, and the reaction was allowed to stir overnight. The mixture wasthen diluted with ether (150 ml) and poured into water (150 ml). Theaqueous phase was extracted twice with ether, and the combined organicextracts were washed with brine, dried over magnesium sulfate, filtered,and concentrated in vacuo. The resulting crude material was thenpurified by column chromatography (silica gel; 5% ethyl acetate/hexanesto 35% ethyl acetate/hexanes) to afford the desired material (11.5 g,22.6 mmol).

Example 25

Benzeneacetic acid,4-[2-(bis[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-, Hydrazide

To a round-bottomed flask containing imidodicarbonic acid,[2-[4-[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-oxoethyl]phenoxy]ethyl]-,bis(1,1-dimethylethyl)ester (3.10 g, 6.09 mmol) in methanol (30 ml) wasadded hydrazine monohydrate (1.03 ml, 21.3 mmol) dropwise. The resultingsolution was allowed to stir at room temperature overnight, and was thenconcentrated in vacuo to an oil. The residue was partitioned betweenmethylene chloride and saturated aqueous sodium bicarbonate, andextracted with methylene chloride. The crude material was purified bycolumn chromatography (silica gel; methylene chloride to 5%methanol/methylene chloride) to afford 1.63 g (65% yield) of the desiredproduct as an oil which crystallized upon standing.

Example 26

Benzeneacetic acid,4-[2-(bis[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-,2-benzoylhydrazide

To a solution of benzeneacetic acid,4-[2-(bis[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-, hydrazide (760mg, 1.86 mmol) in dichloromethane (20 ml) was added benzoyl chloride(0.258 ml, 2.22 mmol) and triethylamine (0.310 ml, 2.22 mmol). Theresulting solution was stirred for about twenty-four hours, quenchedwith saturated aqueous sodium bicarbonate, and extracted with methylenechloride. The combined organic extracts were dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford a crude solid.This material was purified by column chromatography (silica gel; hexanesto 50% ethyl acetate/hexanes) to afford 451 mg (47% yield) of theproduct as a white solid. LRMS ([M−H]⁻)=512.1.

Example 27

2-[4-(5-Phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamine

To a solution of benzeneacetic acid,4-[2-(bis[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-,2-benzoylhydrazide (435 mg, 0.847 mmol) in methylene chloride (12 ml)was added pyridine (0.150 ml, 1.86 mmol). The mixture was cooled toabout −10° C., and triflic anhydride (0.299 ml, 1.78 mmol) was addeddropwise. After the addition was complete, the cold bath was removed andthe reaction mixture was stirred for about an additional one hour. Thereaction was then quenched with saturated aqueous sodium bicarbonate andextracted three times with methylene chloride. The combined extractswere washed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (silica gel; methylene chloride to 20% methanol/methylenechloride) to afford 60 mg (25% yield) of the product amine. LRMS([M+H]⁺)=296.1.

Example 28

6-(4-Fluoro-phenyl)-4,5-dihydro-2H-pyridazin-3-one

In a round-bottomed flask, 4-(4-fluoro-phenyl)-4-oxo-butyric acid (4.90g, 25.0 mmol) and hydrazine hydrate (1.70 ml, 35.0 mmol) were dissolvedin ethanol (50 ml), and the reaction mixture was heated to about 80° C.for about ninety minutes. The mixture was allowed to cool to roomtemperature and then concentrated in vacuo. The resulting solids weresuspended and stirred in ethanol (10 ml) for ten minutes and the mixturewas then filtered to give pure product (4.14 g, 21.5 mmol, 86% yield).LRMS ([M+H]⁺)=193.2; m.p. 191-193° C.

Example 29

6-[4(2-Amino-ethoxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one

In a flame-dried, round-bottomed flask, ethanolamine (1.7 ml, 28.1 mmol)was dissolved in dimethylsulfoxide (9.5 ml), and potassium tert-butoxide(95%, 3.3 g, 28.1 mmol) was added to the solution. This mixture wasstirred at about 65° C. for about ten minutes, and then6-(4-fluorophenyl)-4,5-dihydro-2H-pyridazine-3-one (3.6 g, 18.7 mmol)was added. This dark-colored solution was heated to about 80° C. forabout twelve hours, and was then cooled to room temperature. Water wasadded, and the resulting tan solid was removed by filtration. This crudesolid was then purified by column chromatography (silica gel; 5%methanol/dichloromethane to 15% methanol/dichloromethane) to afford theproduct as a white solid (1.5 g, 34% yield). LRMS ([M+H]⁺)=234.2.

Example 30

1-(4-Methoxy-phenyl)-1H-pyrazole

Copper (II) acetate (960 mg, 5.28 mmol) was added to a flame-dried flaskcharged with pyrazole (240 mg, 3.52 mmol), 4-methoxyphenylboronic acid(1.07 g, 7.04 mmol), 4 A molecular sieves (1.35 activated powder), andpyridine (570 μl, 7.04 mmol) in methylene chloride. The reaction wasstirred for approximately two days at room temperature and then filteredthrough diatomaceous earth. The filtrate was concentrated in vacuo andpurified by column chromatography (silica gel; isocratic 8% ethylacetate/hexanes) to yield 381 mg (2.18 mmol, 62% yield) of the titlecompound. LRMS ([M+H]⁺)=175.2.

Example 31

4 Pyrazole-1-yl-phenol

The title compound of Example 30, 1-(4-Methoxy-phenyl)-1H-pyrazole (400mg, 2.30 mmol), was dissolved in methylene chloride (8 ml) and thesolution was cooled to −78° C. Boron tribromide (1.0 M in methylenechloride, 5.05 ml) was added dropwise to the solution over about fiveminutes to afford a brown-colored solution. The reaction mixture wasallowed to stir for about thirty minutes, the cooling bath was removed,and the mixture was allowed to stir at room temperature for about anadditional three hours. The mixture was poured into water, and theresulting mixture was adjusted to about pH 8. The mixture was extractedwith methylene chloride (3×25 ml), and the combined organic layers weredried over magnesium sulfate, filtered and concentrated in vacuo. Theresulting crude material was purified by column chromatography (25%ethyl acetate/hexanes) to afford 183 mg (50% yield) of the desiredproduct as an oil. LRMS ([M+H]⁺)=161.1.

Example 32

2-(4-Pyrazole-1-yl-phenoxy)-ethylamine

A round-bottomed flask was charged with 4-pyrazole-1-yl-phenol (175 mg,1.09 mmol), and 3.6 ml of toluene, triphenylphosphine (430 mg, 1.64mmol), and benzyl N-(2-hydroxyethyl)carbamate (320 mg, 1.64 mmol) werethen added. The solution was cooled to 0° C. and1,1′-(azodicarbonyl)-dipiperidine (414 mg, 1.64 mmol) was added. Themixture was allowed to stir for about ten minutes at about 0° C. and wasthen allowed to warm to room temperature. An additional 3.6 ml oftoluene and 3.6 ml of tetrahydrofuran were added to the viscoussolution. The reaction mixture was stirred for about forty-eight hours,and the precipitated solids were filtered off and washed with a minimumvolume of 1:1 toluene/tetrahydrofuran. The filtrate was concentrated invacuo to afford the intermediate[2-(4-pyrazole-1-yl-phenoxy)-ethyl]-carbamic acid benzyl ester as an oilwhich was used directly in the next step.

The crude benzyl ester above (1.23 g) was dissolved in methanol (5 ml),and 10% Pd/C (350 mg) and ammonium formate (315 mg, 5.0 mmol) were addedto the resulting mixture. The mixture was allowed to stir for aboutsixteen hours, and was then filtered through diatomaceous earth. Thefiltrate was concentrated to dryness in vacuo, and the residue was thensuspended in water and extracted with ethyl acetate. The combinedextracts were dried over magnesium sulfate, filtered, and concentratedin vacuo. The resulting crude material was purified by columnchromatography (15% methanol/methylene chloride) to afford 130 mg (57%yield for both steps) of desired product.

Example 33

2-[4-(5-Trifluoromethyl-1H-pyrazol-3-yl)-phenoxy]-ethylamine

In a flame-dried, round-bottomed flask, ethanolamine (836 mg, 13.7 mmol)was dissolved in dimethylsulfoxide (2.7 ml), and potassium tert-butoxide(95%, 1.54 g, 13.7 mmol) was added to the solution. This mixture wasstirred at about 65° C. for about ten minutes, and then5-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole (630 mg, 2.74 mmol)was added. The dark-colored solution was heated to about 85° C. forabout eighteen hours, and was then allowed to cool to room temperature.Water was added, and the resulting tan-colored solid was collected byfiltration. This crude product was purified by column chromatography (5%methanol/dichloromethane to 20% methanol/dichloromethane) to afford theproduct as a white solid (255 mg, 25% yield). LRMS ([M+H]⁺)=272.2.

Example 34

4-[1,2,3]Thiadiazol-4-yl-phenol

4-(4-methoxy-phenyl)-[1,2,3]thiadiazole (1.06 g, 5.50 mmol) wasdissolved in methylene chloride (20 ml) and the solution was cooled toabout −78° C. Boron tribromide (1.0 M in methylene chloride, 12.1 ml)was added dropwise to the solution to afford a brown-colored solution.The reaction mixture was allowed to stir for about fifteen minutes, thecooling bath was removed, and the mixture was allowed to stir at roomtemperature for about an additional twelve hours. The mixture was pouredinto water, and the resulting mixture was adjusted to about pH 6. Themixture was extracted with methylene chloride (3×100 ml), and thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford 924 mg (94% yield) of the desired titlecompound as a tan solid. LRMS ([M+H]⁺)=179.1.

Example 35

2-(4-[1,2,3]Thiadiazol-4-yl-phenoxy)-ethylamine

A round-bottomed flask was charged with 4-[1,2,3]thiadiazol-4-yl-phenol(875 mg, 4.90 mmol), and 16 ml of toluene, triphenylphosphine (1.93 g,7.36 mmol), and benzyl N-(2-hydroxyethyl) carbamate (1.44 g, 7.36 mmol)were added. The solution was cooled to 0° C. and1,1′-(azodicarbonyl)-dipiperidine (1.86 g, 7.36 mmol) was added. Themixture was allowed to stir for about ten minutes at about 0° C. and wasthen allowed to warm to room temperature. An additional 16 ml of tolueneand 16 ml of tetrahydrofuran were added to the viscous solution. Thereaction mixture was stirred for about forty-eight hours, and theprecipitated solids were filtered off and washed with a minimum volumeof 1:1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuoto afford crude product which was purified by column chromatography (50%hexanes/ethyl acetate) to provide[2-(4-[1,2,3]thiadiazol-4-phenoxy)-ethyl]-carbamic acid benzyl ester(3.0 g, 57% yield).

The purified benzyl ester above was dissolved in methylene chloride (7ml), and methanesulfonic acid (1.35 ml, 20.9 mmol) was added to thesolution. The resulting solution was heated to about 35° C. for abouttwo hours, and was then diluted with methylene chloride and water. ThepH was adjusted to about 12 with 5N sodium hydroxide, and the mixturewas extracted with methylene chloride. The combined organic extractswere dried over magnesium sulfate, filtered, and concentrated in vacuo.The resulting crude material was purified by column chromatography (20%methanol/methylene chloride) to afford 168 mg (59% yield) of desiredamine product. LRMS ([M+H]⁺)=222.2.

Example 36

4-(4-Methoxy-phenyl)-isoxazole

A round-bottomed flask was charged with potassium carbonate (1.45 g,10.5 mmol) and ethanol (14 ml). To this mixture was added hydroxylaminehydrochloride (730 mg, 10.5 mmol), and2-(4-methoxyphenyl)-malondialdehyde (1.25 g, 7.00 mmol). The reactionmixture was heated at about 80° C. for about three hours. The reactionmixture was then concentrated in vacuo to approximately one-quartervolume and partitioned between water and ethyl acetate. The mixture wasextracted with ethyl acetate and the combined organic extracts weredried over magnesium sulfate, filtered, and concentrated in vacuo to adark oil. This crude material was purified by column chromatography (10%ethyl acetate/hexanes) to afford 1.06 g (86% yield) of the desiredproduct. LRMS ([M−H]⁻)=174.1.

Example 37

4-Isoxazol-4-yl-phenol

To a round-bottomed flask was added D,L-methionine (1.30 g, 8.73 mmol),4-(4-methoxy-phenyl)-isoxazole (1.02 g, 5.82 mmol), and methanesulfonicacid (24 ml). The resulting solution was heated to about 70° C. forabout eighteen hours, and was then allowed to cool to room temperatureand poured onto ice water. The mixture was adjusted to about pH 4, andthe heterogenous mixture was filtered. The solid was washed with waterand then dried to yield the title compound as an off-white solid (640mg, 68% yield). LRMS ([M−H]⁻)=160.0.

Example 38

[2-(4-Isoxazol-4-yl-phenoxy)-ethyl]-Carbamic Acid Benzyl Ester

A round-bottomed flask was charged with 4-isoxazole-4-yl-phenol (570 mg,3.54 mmol), and 12 ml of toluene, triphenylphosphine (1.39 g, 5.30mmol), and benzyl N-(2-hydroxyethyl) carbamate (1.04 g, 5.30 mmol) wereadded. The solution was cooled to about 0° C. and1,1′-(azodicarbonyl)-dipiperidine (1.34 g, 5.30 mmol) was added. Themixture was allowed to stir for about ten minutes at about 0° C., andthe solution was then allowed to warm to room temperature. An additional12 ml of toluene and 12 ml of tetrahydrofuran were added to the viscoussolution. The reaction mixture was stirred for about twenty-four hours,and then the precipitated solids were filtered off and washed with aminimum volume of 1:1 toluene/tetrahydrofuran. The filtrate wasconcentrated to afford the crude product which was purified by columnchromatography (30% ethyl acetate/hexanes) to afford the desired productas a white solid (1.06 g, 88% yield).

Example 39

2(4-Isoxazol-4-yl-phenoxy)-ethylamine

[2-(4-Isoxazol-4-yl-phenoxy)-ethyl]-carbamic acid benzyl ester (1.00 g,2.81 mmol) was dissolved in methylene chloride (14 ml) andmethanesulfonic acid (2.73 ml, 42.2 mmol) was added. The resultingmixture was heated to about 35° C. for about two hours, and was thendiluted with methylene chloride and water. The pH of the mixture wasadjusted to about 12 with 5N sodium hydroxide, and the mixture wasextracted with methylene chloride. The combined extracts were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingcrude product was purified by column chromatography (20%methanol/methylene chloride) to afford 202 mg (53% yield) of the desiredamine. LRMS ([M+H]⁺)=205.3.

The compounds of Formula (I) may be prepared according to the threegeneral preparative methods outlined hereinabove in Schemes I, II andIII, denoted hereinbelow as Method A, Method B, and Method C,respectively, using appropriate synthetic precursors, including thoseprecursors disclosed hereinabove in Examples 1 through 38, or thoseanalogous thereto.

Method A (Scheme I)

(R)-1-(6-Chloro-pyridin-3-yl)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol

In a round-bottomed flask, (R)-2-chloro-5-oxiranyl-pyridine (U.S. Pat.No. 5,541,197) (73.0 mg, 0.477 mmol) and the title compound of Example 4(2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamine) (212 mg, 0.716 mmol)were dissolved in 5 ml of ethanol, and the mixture was heated to about80° C. for about sixteen hours. The solution was then concentrated invacuo to an oil, and the crude material was purified by columnchromatography (methylene chloride to 2% methylene chloride/methanol) toafford 107 mg (0.236 mmol, 50%) of the title compound as a white solid.LRMS ([M+H]⁺)=452.2.

Utilizing appropriate starting materials, the following compounds wereprepared in a manner analogous to that employed for the preparation ofthe title compound of Method A:

(R)-2-{2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-(6-chloro-pyridin-3-yl)-ethanol;

(R)-2-{2-[4-(4-biphenyl-4-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-(6-chloro-pyridin-3-yl)-ethanol;

(R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-(6-chloro-pyridin-3-yl)-ethanol;

(R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-(6-chloro-pyridin-3-yl)-ethanol;

(R)-N-[2-chloro-5-(2-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(2-{1,1-dimethyl-2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-(2-chloro-5-(2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-1,1-dimethyl-ethylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-(2-chloro-5-{1-hydroxy-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-(2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-N-(2-chloro-5-{1-hydroxy-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethyl}-phenyl)-methanesulfonamide;

(R)-N-[2-chloro-5-(1-hydroxy-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-cyclopentyl-thiazol-4-y)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-[1,1-dimethyl-2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-[1,1-dimethyl-2-(4-oxazol-5-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{1,1-dimethyl-2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-2-[3-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-1-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-1,1-dimethyl-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl-phenoxy}-ethylamino)-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-³-yl)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[3-(2-methyl-thiazol-4-y)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(5-methyl-1H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyidin-3-yl)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-phenethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[3-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-y)-2-{2-[3-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[3-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-y)-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-(2-{3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;and

(R)-1-(6-chloro-pyridin-3-yl)-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol.

Method B (Scheme II)

(R)-N-[5-(1-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide

In a round-bottomed flask,2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamine (175 mg, 0.747 mmol)and toluene-4-sulfonic acid2-(6-acetylamino-pyridin-3-yl)-2-(tert-butyl-dimethyl-silanyloxy)-ethylester (231 mg, 0.498 mmol) were dissolved in dimethylsulfoxide (0.50mL), and diisopropyl ethyl amine (0.105 mL, 0.600 mmol) was added in oneportion. The resulting mixture was heated to about 80° C. for aboutsixteen hours, and was then partitioned between diethyl ether and water.The aqueous phase was extracted with diethyl ether four times, and thecombined organic extracts were then washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingwhite solid was purified by column chromatography (methylene chloride to10% methanol/methylene chloride) to afford 117 mg (45%) of the desiredproduct. LRMS ([M+1]⁺): 527.1.

(R)-N-[5-(1-Hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide

To a solution of(R)-N-[5-(1-(tert-butyl-dimethyl-silanyloxy)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide(115 mg, 0.218 mmol) in tetrahydrofuran (1.5 mL) was addedtetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.65 mL, 0.65mmol) at room temperature. The resulting solution was allowed to stirfor about two and one-half hours, and the reaction mixture was thenpartitioned between ethyl acetate and water. The pH of the mixture wasadjusted to about 10-11, and the aqueous phase was then extracted withethyl acetate. The combined organic extracts were washed with brine,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresulting crude material was purified by column chromatography(methylene chloride to 20% methanol/methylene chloride) to afford 75 mg(83%) of the desired product. LRMS ([M+1]⁺): 413.2.

(R)-1-(6-Amino-pyridin-3-yl)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol

In a round-bottomed flask,(R)-N-[5-(1-hydroxy-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethyl)-pyridin-2-yl]-acetamide(74 mg, 0.18 mmol) was dissolved in 1.0 mL of ethanol, and 1.0 mL of 2 Msodium hydroxide was added to the solution. The reaction mixture wasthen heated to about 80° C. for about twenty minutes, and was thendiluted with water and adjusted to about pH 11. The aqueous phase wasextracted with four portions of methylene chloride, and the combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting crude material was purified bycolumn chromatography (methylene chloride to 20% methanol/methylenechloride) to afford 49 mg (74%) of the desired product. LRMS ([M+1]⁺):371.2.

Method C (Scheme III)

2-{2-[4-(4-Phenyl-thiazol-2-yl)-phenoxyl-ethylamino}-1-pyridin-3-yl-ethanol

In a nitrogen-purged round-bottomed flask,1-(6-chloro-pyridin-3-yl)-2-{2-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol(107 mg, 236 mmol) was dissolved in a mixture of methanol (2.3 ml), THF(0.5 ml), and ethyl acetate (0.5 ml). Palladium on carbon (10%, 107 mg,100 wt %) and ammonium formate (149 mg, 2.36 mmol) were then addedsequentially. The reaction mixture was stirred overnight, filteredthrough diatomaceous earth, and the filter cake rinsed with ethylacetate. The filtrate was concentrated to a white solid, which waspurified by column chromatography (methylene chloride to 4%methanol/methylene chloride) to afford a pale yellow solid (44 mg, 44%).LRMS ([M+H]⁺)=418.3.

Utilizing appropriate starting materials, the following compounds wereprepared in a manner analogous to that employed for the preparation ofthe title compound of Method C:

(R)-1-(6-amino-pyridin-3-yl)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[3-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[3-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-[2-(4-[1,2,3]thiadiazol-5-ylphenoxy)-ethylamino]-ethanol;

(R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(4H[1,2,4-]triazol-3-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-(2-{3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

(R)-1-pyridin-3-yl-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(5-trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]-ethylamino}-ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;ethanol;

(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenyl]-ethylamino}-ethanol;

(R)-2-{2-[4-(2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{1,1-dimethyl-2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-[1,1-dimethyl-2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-[1,1-dimethyl-2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-{1,1-dimethyl-2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

(R)-2-{2-[3-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-1,1-dimethyl-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-6-{4-[2-(2-hydroxy-2-pyridin-3-yl-ethylamino)-ethoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one;

(R)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2′-methyl-[2,4′]bithiazolyl-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-[2-(3-methyl-4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-oxazol4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(5-methyl-oxazol-4-yl)-phenoxyl-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(5-methyl-1H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[3-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-[2-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-[2-(4-oxazol-2-yl-phenoxy)-ethylamino]-1-pyridin-3-ylethanol;

(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-phenethyl-thiazol-4-yl)-phenoxyl-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[3-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;

(R)-2-[2-(4-pyrazol-3-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;and

(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol.

Salt Formation

The hydrochloride salt forms of the compounds of Formula (I) may beprepared according to the following example.

The compound(R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol(40 mg, 0.095 mmol) was dissolved in about 3 ml of methylene chloride,and 1.0 M HCl in diethylether (0.28 ml, 0.28 mmol) was added to thesolution dropwise. The resulting cloudy suspension was concentrated invacuo to afford 47 mg of a white solid.

Biological Assays

The utility of the compounds of Formula (I), the stereoisomers andprodrugs thereof, and the pharmaceutically acceptable salts of thecompounds, stereoisomers, and prodrugs in the practice of the instantinvention, can be evidenced by activity in at least one of the protocolsdescribed hereinbelow.

Assay 1

β₃ Receptor Selectivity Over β₁ and β₂ Adrenergic Receptors

In vitro β₃ receptor agonist activity and selectivity over β₁ and β₂adrenergic receptors may be determined by measurement of cyclicadenosine monophosphate (cAMP) accumulation in Chinese hamster ovarycells.

Chinese hamster ovary cells uniquely transfected with the cDNA for thehuman β₁, β₂, or β₃ adrenergic receptor are grown to confluence in Ham'sF12 media (Gibco BRL, Life Technologies, Inc., Grand Island, N.Y.)containing 10% fetal bovine serum, 500 mg/ml geneticin, 100 U/mlpenicillin, 100 mg/ml streptomycin, and 250 ng/ml fungizone according tothe procedure described in American Type Culture Catalog of Cell Linesand Hybridomas, Seventh Edition, 1992, p. 36, ATCC CCL 61 CHO-K1.Compounds are prepared as 25 mM stock solutions in DMSO (0.1% DMSO finalconcentration), diluted in Ham's F12 media and added to the cells at10⁻¹⁰ to 10⁻⁵ M along with 10⁻⁵ M isobutylmethylxanthine to inhibitphosphodiesterase activity. The media and cells are then incubated forsixty minutes at 37° C. At the end of the incubation period, the mediais aspirated and the cells lysed in 0.01 N HCl. The cellular content ofcAMP is then determined by radioimmunoassay (RIA) using a kit from NewEngland Nuclear (Burlington, Mass.). There is a direct correlationbetween the cellular content of cAMP and the agonism of the β₁, β₂, orβ₃ adrenergic receptor. The non-selective, full β-adrenergic agonistisoproterenol is included as a positive control at 10⁻⁵ M.

Assay 2

Many G protein-coupled receptors (GPCRs) exhibit at least two agonistaffinity states. High affinity agonist binding to GPCRs requires theassociation or coupling of the receptor with the GDP-boundheterotrimeric G protein complex. In general, the low affinity agonistbinding site is indicative of the uncoupled receptor state. The highaffinity agonist binding site can be converted to the low affinity siteby addition of GTP or its analogs. In the absence of agonist, G proteinsdisplay high affinity for GDP. In the presence of agonist, G proteinsdisplay high affinity for GTP. Thus, when agonist and GTP are added tothe receptor/G protein complex, GTP displaces GDP and uncouples thereceptor from the G protein. Two affinity states for agonists can bedetected in radioligand comptetetion binding assays. A two-site fit isgenerally observed for agonists for many GPCRs and can be calculatedusing commercially available software. The high affinity site (K_(iH))corresponds to the G protein-coupled state and, in the case ofβ₃-adrenergic receptors correlates well with the functional ED₅₀ forstimulation of cAMP accumulation.

In order to identify compounds that attenuate the binding of[¹²⁵I]cyanopindolol (ICYP) to β₃ adrenergic receptors, the followingradioligand binding assay can be used.

Radioligand Binding Assays

ICYP β₃ Adrenergic Receptor Competition Binding Assay

The specific activity of [¹²⁵I]CYP is 2000 Ci/mmole. ICYP undergoescatastrophic decay upon radiolysis. Therefore, the specific activityalways remains at 2000 Ci/mmole, but the concentration will decreaseover time. The final concentration of ICYP is 250 pM. Therefore, a 2.5nM (10×) stock needs to be made. [¹²⁵I]CYP can be obtained from NewEngland Nuclear, Boston, Mass.

Competitors

Up to four compounds can be tested in thirteen competition curves in a96 well format. An example for a single compound is outlined below.

[Comp 1]

A 1,2 −10

B 1,2 −9.3

C 1,2 −9

D 1,2 −8.3

E 1,2 −8

F 1,2 −7.3

G 1,2 −7

H 1,2 −6.3

A 3,4 −6

B 3,4 −5

C 3,4 −4

D 1,3 pindolol

E 3,4 TOTAL

The next compound would begin in F 3,4. Two pairs of totals andnon-specific binding are added to the plates.

Wells E 3,4 and G 7,8 are for total cpm bound.

Wells D 3,4 and H 7,8 are for 100 μM pindolol to determine non-specificbinding.

To each well in order add:

20 μl buffer to “total” wells

20 μl 1 mM pindolol to pindolol wells

20 μl of each concentration of compound to the appropriate wells

20 μl of 2.5 nM ICYP to all wells

160 μl membranes diluted to 15 μg/160 μl

Procedure

1. Set up assay for Packard 96 well Unifilter with GF/C filters(Packard; Meriden, Conn.) using a 96 well microtiter plate.

2. Incubate 90-120 minutes with shaking at room temperature

3. Using Packard cell harvester (Packard; Meriden, Conn.), aspiratesamples into processing head. Use a pre-soaked (0.3% PEI) filter.

4. Wash four times with cold wash buffer.

5. Dry plate, and add 25 μl Microscint (ICN Manufacturers; Costa Mesa,Calif.) to each well.

6. Count samples in Wallac beta plate reader (Wallac; Turku, Finland).

Binding Buffer

50 mM Hepes/10 mM MgCl₂, pH 7.4 (prepared from 10× stock solution) 0.2%BSA (fraction V)

Protease inhibitors (prepared as 100×stock solution)

100 μg/ml bacitracin

100 μg/ml benzamidine

5 μg/ml aprotin

5 μg/ml leupeptin

Wash Buffer

50 nM Hepes/10 mM MgCl₂, pH 7.4, ice cold (prepared from 10×stocksolution)

Assay 3

Oxygen Consumption

As will be well known to one of ordinary skill in the art, duringincreased energy expenditure, animals generally consume increasedamounts of oxygen. In addition, metabolic fuels such as, for example,glucose and fatty acids, are oxidized to CO₂ and H₂O with theconcomitant evolution of heat, an effect commonly referred to in the artas thermogenesis. Accordingly, the measurement of oxygen consumption inanimals, including humans and companion animals, is an indirect measureof thermogenesis, and indirect calorimetry may be commonly used inanimals, e.g., humans, by one of ordinary skill in the art, to measuresuch energy expenditures.

The ability of the compounds of Formula (I), the stereoisomers andprodrugs thereof, and the pharmaceutically acceptable salts of thecompounds, stereoisomers, and prodrugs, to generate a thermogenicresponse may be demonstrated according to the following protocol usingmale Sprague-Dawley rats (Charles River, Wilmington, Mass.).

Whole animal oxygen consumption may be measured using an open circuit,indirect calorimeter (Oxymax™, Columbus Instruments, Columbus, Ohio).The gas sensors are calibrated with nitrogen gas and gas mixture (0.5%carbon dioxide, 20.5% oxygen, 79% nitrogen; Abco Industrial Supplies,Waterford, Conn.) before each experiment. Male Sprague-Dawley rats(300-380 g body weight) are placed in sealed chambers (43×43×10 cm) ofthe calorimeter and the chambers placed in activity monitors. Air flowrate through the chambers is set at 1.6-1.7 I/min. The calorimetersoftware calculates the oxygen consumption (ml/kg/hour) based on theflow rate of air through the chambers and the difference in oxygencontent at inlet and outlet ports. The activity monitors have fifteeninfrared light beams spaced one inch apart on each axis; ambulatoryactivity is recorded when two consecutive beams are broken (repeatedinterruptions of the same beam are not registered) and the results arerecorded as counts. Basal oxygen consumption and ambulatory activity aremeasured every ten minutes for two and one-half to three hours. At theend of the basal period, the chambers are opened and the test compound(0.01-20 mg/kg, prepared in water, 0.5% methyl cellulose, or othersuitable vehicle) or an equivalent amount of vehicle is administered byoral gavage. Oxygen consumption and amulatory activity are measuredevery ten minutes for an additional two to six hours post-dosing.Percent change in oxygen consumption is calculated by averaging thepost-dosing values and dividing by basal oxygen consumption (average ofthe pre-dosing values except the first hour). Oxygen consumption valuesobtained during time periods where ambulatory activity exceeds 100counts are excluded from the calculation. Thus, the values represent %change in resting oxygen consumption.

Assay 4

Hypoglycemic Activity

The compounds of Formula (I) may be tested for hypoglycemic activityaccoprding to the following procedure, and as an aid in determiningdosages when compared to other test compounds and standards.

Five to eight-week old C57 BL/6J-ob/ob mice (Jackson Laboratory, BarHarbor, Me.) are housed five animals per cage at an ambient temperatureof 66° C. under standard animal care practices. After a one weekacclimation period, the animals are weighed and 25 microliters of bloodis collected via an occular bleed prior to any treatment. The bloodsample is immediately diluted 1:5 with saline containing 2% sodiumheparin, in tubes held on ice. Blood samples are centrifuged for twominutes to remove red blood cells and the supernatant is analyzed forglucose concentration using a clinical autoanalyzer (Abbott Spectrum®CCx; Abbott Laboratories, Abbott Park, Ill.). Animals are thenregrouped, in groups of five animals per cage, such that the meanglucose values of the groups are similar. The mice are then dosed onceor twice daily for five days with test compound (0.01-20 mg/kg), with apositive control such as englitazone or ciglitazone (50 mg/kg p.o.)(U.S. Pat. No. 4,467,902; Sohda et al., Chem. Pharm. Bull., 32,4460-4465, (1984)), or with vehicle. All compounds are administered byoral gavage in a vehicle consisting of 0.5% w/v methyl cellulose, orwith other suitable vehicle. On Day 5, the animals are weighed again andbled (via the occular route) for blood glucose levels as describedhereinabove. Plasma glucose is then calculated by the equation:

Plasma Glucose (mg/dl)=Sample Value×5×1.67=8.35×Sample Value where 5 isthe dilution factor and 1.67 is the plasma hematocrit adjustment(assuming the hematocrit is 40%).

The animals dosed with vehicle maintain substantially unchangedhyperglycemic glucose levels (e.g. 300 mg/dl), while positive controlanimals have depressed glucose levels (e.g. 130 mg/dl). The glucoselowering activity of test compounds is expressed in terms of % glucosenormalization. For example, a glucose level which is the same as thepositive control is expressed as 100%.

Assay 5

β₁ and β₂ Receptor Selectivity

In vivo selectivity for β₁ and β₂ receptors may be determined bymeasurements of heart rate, blood pressure, and plasma potassiumconcentration gathered on conscious catheterized rats (male,Sprague-Dawley, 300-400 g body weight). To implant catheters, rats areanesthetized with pentobarbital (50-60 mg/kg i.p.) and the left carotidartery is cannulated with PE50 tubing. The catheter is tunneledsubcutaneously, exteriorized at the back of the neck, filled with asolution of polyvinylpyrrolidone in heparinzied saline, flame sealed,and taped. Experiments are performed seven days after surgery. On theday of the experiment, the catheters are untaped and flushed withsaline. After at least thirty minutes, basal values for heart rate andblood pressure are measured by attaching the catheter to a pressuretransducer, the results recorded on a Grass Model 7 polygraph (GrassMedical Instruments, Quincy, Mass.), and a basal blood sample (0.5 ml)is obtained from the arterial catheter. After obtaining basal values,the test compound or vehicle is administered by oral gavage and bloodpressure (measure of β₂ activity) and heart rate (measure of β₁activity) measurements are taken at 15, 30, 45, and 60 minutes, andblood samples for potassium determination (β₂) are obtained at 30 and 60minutes. Isoproterenol, a non-selective β-agonist, can be tested as apositive control at doses ranging from 0.001 to 1 mg/kg (injected s.c.in saline vehicle). Plasma potassium is determined by flamespectrophotometry. To determine changes, basal values are subtractedfrom the average of the post-dosing values.

Assay 6

Reducing Intestinal Motility

The compounds of Formula (I) have the effect of reducing intestinalmotility and thus have utility in aiding in the treatment of variousgastrointestinal disorders such as irritable bowel syndrome, pepticulceration, esophagitis, gastritis, duodenitis (including that inducedby Helicobacter pylori), intestinal ulcerations (including inflammatorybowel disease, ulcerative colitis, Crohn's Disease and proctitis), andgastrointestinal ulcerations. It has been proposed that the motility ofnon-sphincteric smooth muscle contraction is mediated by activity at β₃adrenergic receptors. The availability of a β₃ specific agonist, withlittle activity at β₁ and β₂ receptors, will assist in the pharmacologiccontrol of intestinal motility without concurrent cardiovasculareffects.

In vivo activity of the compounds of Formula (I) for the treatment orprevention of intestinal motility disorders can be determined accordingto the following procedures. Eighteen-hour fasted male Sprague-Dawleyderived (CD) rats (175-225 g) are dosed with 0.01-20 mg/kg p.o. of testcompound or vehicle (distilled water). Thirty minutes afteradministration of test compound, the rats are orally dosed with 0.25 mlof a solution of sodium chromate in 0.9% saline containing about 20,000cpm of ⁵¹Cr (specific activity 350 mCi/mg Cr). Twenty minutes later, therats are sacrificed, the gastroesophageal, pyloric, and ileocecaljunctions are then ligated, and the stomachs and small intestines areremoved. The small intestines are then divided into ten equal lengths,and the stomach and each length of intestine assayed for radioactivitywith a gamma counter. Gastric emptying rate may then be determined foreach rat by comparing the amount of radioactivity in the intestinerelative to the total in the intestine plus stomach. In addition, thegeometric center of the distribution of the radioactive marker is thenused as a measure of the overall transit rate through the stomach andintestine. The geometric center is calculated by summing the products ofthe fractions of ⁵¹Cr in each segment times the segments number:geometric center=S ((fraction of ⁵¹Cr per segment)×(segment number)).For these calculations, the stomach is considered segment number 0, andand the ten intestinal segments as numbers 1 to 10. Thus, a geometriccenter of 0.0 indicates that the entire load of ⁵¹Cr remains in thestomach. Data from the two experiments are pooled, and statisticalevaluations are made using Dunnett's multiple comparison test.

Alternatively, in groups of eight, overnight-fasted male Sprague-Dawley(CD) rats (175-225 g) may be anesthetized with methoxyflurane. A smallabdominal incision is then made, and the pylorus ligated. Immediatelyafter the ligation, a solution of the test compound or vehicle(distilled water) is injected into the proximal duodenum. The doses oftest compound used should be 0.01-20 mg/kg body weight. The incisionsare then closed and the rats allowed to recover from the anesthesia. Twohours after the ligation, the rats are sacrificed and the gastric fluidcollected and cleared by centrifugation. Total volume of secretion isdetermined by weight, and acidity is determined by titration to pH 7.0with 0.1 N sodium hydroxide using an automatic titrator. The data fromtwo experiments are then pooled. A group of rats treated with 10 mg/kgof of the anti-secretory histamine H₂-receptor antagonist cimetidine maybe included as a positive control. Statistical evaluations can be madeusing Student's t-test.

In vitro activity for relaxation of contracted ileum from isolatedguinea pig ileum is determined according to the following procedures.Fresh, isolated segments of guinea pig ileum (about 1.5 cm in length)are mounted in tissue baths containing Tyrode's physiological saltsolution at about 30° C. and aerated continuously with oxygen:carbondioxide (95%:5%). Tissues are then equilibrated for 60-90 minutes under4.0 gm tension in order to achieve stable baselines. Histamine is thenadded to the baths and in a cumulative fashion in concentrations rangingfrom 1 nM to 10 mM. The maximum tension generated after each addition ofhistamine is recorded on a Grass Physiograph (Grass Medical Instruments,Quincy, Mass.). The tissues are then washed with several changes ofTyrode's solution, basal tension is readjusted to 4.0 gm, and a stablebaseline is then again obtained. Each tissue is then exposed to a singleconcentration of a test compound (1 nM-10 mM) or vehicle and, after athirty minute equilibration period, the histamine dose response curve isthen repeated. Results from multiple experiments are standardized(0-100%) to the maximum response of the control tissues and plotted aspercent maximum tension vs. the log of the histamine concentration inthe absence and presence of the test compound.

Assay 7

Protection Against Gastric Ulceration

Food (but not water) is withheld from female Sprague-Dawley rats(Charles River, Wilmington, Mass.) weighing 70-120 g. Access is thenpermitted to food for ninety minutes. A single dose of test compound isthen administered p.o. (0.01-20 mg/kg in a dosing volume of 1 ml/100 g),and indomethacin (Sigma Chemical Co., St. Louis, Mo.) (60 mg/kg, 1ml/100 g body weight) is then injected subcutaneously. Control ratsreceive the subcutaneous injection of indomethacin and oraladministration of vehicle (0.5% methyl cellulose in distilled water) forthe β-adrenoceptor agonist. The animals are then allowed continuedaccess to food but water is withdrawn. The animals are then sacrificedby cervical dislocation six hours after dosing with indomethacin. Thestomach are then removed, opened along the greater curvature and washedin 0.9% saline. An assessment of gastric damage is carried out by anobserver who is unaware of the dosing regimen. A transparent plasticgrid divided into 1 mm² sections is placed over the antrum and the areaof macroscopic damage assessed as the total area of visible lesions inmm². This value is then expressed as a percentage of the total antralarea.

Assay 8

Anti-Depressant Activity

Male CD1 mice weighing between 20 and 25 g, and Sprague-Dawley ratsweighing between 200 and 250 g are obtained from Charles River,Wilmington, Mass. Test compounds of Formula (I) are dissolved in water.The compounds are administered to mice in a volume of 10 ml/kg, and torats in a volume of 2 ml/kg. Control animals receive the vehicle.Positive test results for the following parameters indicateanti-depressant activity.

(1) Antagonism of Hypothermia Induced by Reserpine

Mice are administered reserpine (2.5 mg/kg i.p. dissolved in 1% citricacid). Their rectal temperatures are measured three and one-half hourslater. The mice are then divided into different groups so as to obtainthe same mean rectal temperature in each group. One-half hour later,(i.e., four hours after reserpine administration), the mice are giventhe vehicle or test compound. Rectal temperature is measured againninety minutes later (i.e., five hours and thirty minutes afterreserpine administration) (Bourin, et al., The Value of the ReserpineTest in Psychopharmacology, Arzneim. Forsch., 33, 1173, (1983)).

(2) Antagonism of Hypothermia Induced by Apomorphine

One-half hour after the mice are placed in individual cages, theirrectal temperatures are recorded. The animals are allocated so as toobtain the same mean rectal temperature in each group. Apomorphine (16mg/kg s.c.) is given thirty minutes after the test compound or vehicle.Rectal temperature is then measured again thirty minutes after theapomorphine treatment (Puech, et al., Antagonism of Hypothermia andBehavioral Response to Apomorphine; A Simple, Rapid, and DiscriminatingTest for Screening Anti-Depressants and Neuroleptics,Psychopharmacology, 75, 84, (1981)).

(3) Effect on Learned Helplessness Behavior

This test is performed essentially as described by Giral, et al.,Reversal of Helpless Behavior in Rats by Putative 5-HT_(1A) Agonists,Biol. Psychiat., 23, 237 (1988). Electric footshocks are delivered tomale albino Sprague-Dawley rats placed in chambers (20×10×10) withPlexiglass® walls and covers. The floors are made of stainless-steelgrids (1.5 cm mesh). A constant-current shock is delivered as sixtyscrambled, randomized inescapable shocks (15 sec. duration, 0.8 mA,every 60+15 sec.) to the grid floor. Control rats are then placed inidentical chambers, but no shock is administered. All preconditioningtrials are performed on Day 1 between 9 and 11 a.m. Avoidance trainingis initiated 48 h (Day 3) after inescapable shock in automated two-wayshuttle boxes (60×21×30 cm) with Plexiglass® walls and a floorconsisting of stainless-steel rods spaced 1.0 cm apart in order toevaluate escape deficits. Each shuttle box is divided into two chambersof equal size by a stainless-steel partition with a gate providingaccess to the adjacent compartment through a 7×7 cm space. Shuttle boxsessions are performed for three consecutive days (Days 3, 4, and 5).The animals are placed individually in the shuttle box and allowed tohabituate to the environment for five minutes (for the first sessiononly) and then subjected to thirty trials. The intertrial intervalshould be thirty seconds. A light signal, used as a conditionedstimulus, is presented during the first three seconds of each trial.Crossing the gate into the other compartment of the box during this“conditioned stimulus only” period (referred to as avoidance response)allows rats to avoid shocks. A period with conditioned stimulus plusfoot-shock (0.8 mA) may be presented if an avoidance response does notoccur. Crossing the gate into the other compartment during thisconditioned stimulus plus shock period is referred to as an escaperesponse. Absence of escape response during the three-second durationconditioned stimulus plus shock is considered to be an escape failure.

The rats (n=10 per group) are treated randomly according to one of thefollowing protocols: the control sample, which receives no shock, and isgiven only vehicle, or experimental animals with inescapable shock aretreated daily with vehicle or test compound. Animals are treated orallyover five consecutive days, i.e. six hours after shock pretreatment onDay 1, and then twice per day, a half dose in the morning (30 minutesbefore shuttle box session) and half a dose in the afternoon (except onday 5). Statistical analysis is performed on the mean number of escapefailures using a two-way analysis of variance (subjects×sessions)followed by Dunnett's test.

Assay 9

Bronchial Relaxation and Ciliary Motility

In vitro activity of the compounds of Formula (I) for the treatment ofairway inflammatory disorders, such as asthma and obstructive lungdisease, may be determined by measurement of guinea pig bronchial ringrelaxation according to the following procedure.

Guniea pig bronchial rings are obtained from tricolored guinea pigs ofeither sex (250-350 g), anesthized with urethane (1.25 g/kg) andsuspended under an initial tension of 2.0 g in Krebs solution at 37° C.gassed with 95% oxygen:5% carbon dioxide. After about one hour ofequilibration, the guinea pig bronchial rings are contracted withacetylcholine (10-3 M), relaxed to maximal relaxation with theophylline(10-3 M), and then allowed to equilibrate for a further sixty minuteswhile they are washed with Krebs solution every fifteen minutes.

Changes in tension are measured isometrically with strain guages andamplifiers and displayed on a recorder. The composition of the Krebssolution is (mM):NaCl 118.0, FCl 5.4, CaCl₂, 2.5, KHPO₄ 1.2, MgSO₄ 1.2,NaHCO₃ 25.0, and glucose 11.7.

To test effects of test compounds on resting tension, cumulativeconcentration-response curves are obtained by addition of the testcompounds (10⁻⁹-10⁻⁶ M) every ten to twenty minutes until a plateau isreached. The relaxant effects of the test compounds are expresed aspercentages of the maximal relaxations induced by theophylline (3×10⁻³M).

Assay 10

Prostate Disease

Ventral prostates of male Sprague-Dawley rats (300-400 g) anesthetizedwith diethyl ether are quickly excised and placed in oxygenated Krebssolution. While maintained at room temperature in this buffer, adherentfatty and connective tissues are removed. The prostates are thensuspended in 10 ml organ baths containing Krebs solution warmed to 37°C. and aerated with a mixture of 95% oxygen and 5% carbon dioxide. Thecomposition of the Krebs solution is 118.4 mM NaCl, 4.7 mM KCl, 1.2 mMMgSO₄, 2.5 mM CaCl₂, 11.1 mM dextrose, 25.0 mM NaHCO₃ and 1.2 mM KH₂PO₄,dissolved in distilled and demineralized water. The tissues are attachedto isometric force-displacement transducers and isometric contraction isrecorded under a loading tension of 0.5 g. Equilibration is undertakenfor one or two hours before the addition of test compounds. Submaximalcontractions are first elicited by repeated concentrations of 1×10⁻⁶Mphenylephrine until constant responses are obtained. The control andtest compound-treated experiments are performed in differentpreparations. A concentration-response curve to cumulate concentrationsof phenylephrine or acetylcholine (10⁻⁹ to 10⁻⁴M) is determined. Fortesting compounds, a concentration response curve to phenylephrine oracetylcholine is determined in the presence of the compounds.

In vitro activity of compounds of Formula (I) can also be determined forspecific efficacy in human prostate as follows.

Prostatic tissue specimens are obtained from patients with symptomaticBPH, who are undergoing open prostatectomy. Isolated human prostatictissue is cut into five to eight strips (3 mm wide, 3 mm thick and 15 mmlong in each strip). The strips are mounted vertically in organ bathscontaining 20 ml Krebs-Henseleit solution of the following composition(mM): NaCl 112, KCl 5.9, MgCl₂ 1.2, CaCl₂ 2, NaHCO₃ 25, NaHPO₄ 1.2,glucose 11.5. The medium is maintained at 37° C. and at pH 7.4, and isequilibrated with a gas mixture consisting of 95% oxygen and 5% carbondioxide. A resting tension of 0.5 g is applied and the responses arerecorded isometrically through a force-displacement transducer. Thepreparations are equilibrated for ninety minutes before starting theexperiments.

Concentration-response curves for phenylephrine or acetylcholine (10⁻⁹to 10⁻⁴M) are determined by adding the compound directly to the bathingmedia in a cumulative fashion. For testing compounds, the prostatestrips are incubated in the presence of compound (1 or 10 μM) for thirtyminutes before and then phenylephrine or acetylcholine are added to themedium in a cumulative fashion to obtain to the concentration-responsecurve in the presence of the compound.

Assay 11

Effect on Triglyceride Levels and Dyslipidemia

Compounds of the Formula (I) lower triglyceride levels and cholesterollevels and raise high density lipoprotein levels and are therefore ofuse in combating medical conditions wherein such lowering (and raising)is thought to be beneficial. Thus, the compounds of Formula (I) can beused in the treatment of hypertriglyceridaemia, hypercholesterolemia,and conditions of low HDL (high density lipoprotein) levels in additionto the treatment of atherosclerotic disease such as of coronary,cerebrovascular and peripheral arteries, cardiovascular disease andrelated conditions.

Activity of compounds of Formula (I) for dyslipidemia can be determinedaccording to the following procedure. C57BL/6J ob/ob mice (male, 30-40 gbody weight, Jackson Lab, Bar Harbor, Me.), housed 5 mice per cage in anenvironmentally controlled room, are dosed once or twice daily for threeweeks with test compound (0.01-20 mg/kg, n=15 per group) or vehicle(0.5% w/v methyl cellulose/distilled water, water, or other suitablevehicle) by oral gavage. At the end of the study, twenty-four hoursafter giving the final dose of compound, the mice are sacrificed bydecapitation and blood collected. Plasma concentrations of free fattyacids and triglyceride are determined using a clinical autoanalyzer(Abbott Spectrum® CCx; Abbott Laboratories, Abbott Park, Ill.).

Assay 12

Decrease in Body Fat

Activity of compounds of Formula (I) for decrease in body fat can bedetermined according to the following procedure. C57BL/6J ob/ob mice(male, 30-40 g body weight, Jackson Lab, Bar Harbor, Me.) are housedfive mice per cage in an environmentally controlled room with food(pelleted rodent chow) and water available ad libitum. The compound orvehicle (0.5% w/v methyl cellulose/distilled water, water, or othersuitable vehicle) is dosed once or twice daily for three weeks (0.01-20mg/kg, n=15 per group) by oral gavage. Body weight of each mouse ismeasured daily and food intake per cage determined by weighing theamount of food left in the trough. At the end of the study, twenty-fourhours after giving the final dose of compound, the mice are weighed andthen sacrificed by cervical dislocation. The epididymal fat pads fromeach mouse are excised and weighed. The fat versus body weight ratio isdetermined for each mouse using the absolute body weights and the fatpad weights. A reduction in fat pad weight is indicative of a reductionin total body fat.

What is claimed is:
 1. A compound of Formula (I)

the stereoisomers thereof, and the pharmaceutically acceptable salts ofsaid compounds, stereoisomers, wherein: Ar is pyridyl; R is hydrogen,hydroxy, halogen, —CF₃, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,—(C₃-C₈)cycloalkyl, —NR₉R₁₀, —NR₉SO₂R₁₀, —NR₉COR₁₀, or —SO₂R₉; R₁ ishydrogen, —(C₁-C₆)alkyl, halogen, —(C₁-C₆)alkoxy, or hydroxy; R₂, R₃, R₄are, independently, hydrogen, or —(C₁-C₆)alkyl; R₅ is a aromatic5-membered ring heterocycle having from 1 to 4 heteroatoms selected fromthe group consisting of oxygen, sulfur, or nitrogen; R₆ and R₇ are,independently, hydrogen, halogen, cyano, oxo, —(C₁-C₆)acyl, —CO₂R₉,—NR₉R₁₀, hydroxy, —(C₁-C₆)alkoxy, —CONR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, or—SO₂R₉; —(C₁-C₆)alkyl, optionally substituted with —(C₃-C₈)cycloalkyl,halogen, aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl, alkylalkoxy, hydroxy,—NR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, or heterocycle;—(C₃-C₈)cycloalkyl, optionally substituted with —(C₁-C₆)alkyl,—(C₃-C₈)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl,alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, orheterocycle; aryl, optionally substituted with —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl,alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, orheterocycle; or heterocycle, optionally substituted with —(C₁-C₆)alkyl,—(C₃-C₈)cycloalkyl, halogen, aryl, —(C₁-C₆)alkoxy, —(C₁-C₆)haloalkyl,alkylalkoxy, hydroxy, —NR₉R₁₀, —NR₉SO₂R₁₀, —SO₂NR₉R₁₀, —SO₂R₉, orheterocycle; R₈ is hydrogen, —(C₁-C₄)alkyl, or halogen; and R₉ and R₁₀are, independently, hydrogen, —(C₁-C₆)alkyl, alkylalkoxy,—(C₃—C₈)cycloalkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkoxy, aryl, orheterocycle; X is a direct bond or oxygen; and Y is a direct bond,—(C₁-C₆)alkyl, —OCH₂—, —CH₂O—, or oxygen.
 2. A compound according toclaim 1, wherein Ar is pyridyl; R, R₁, R₂, R₃, R₄, and R₈ are hydrogen;X is oxygen; Y is a direct bond; and R₅ is an aromatic 5-membered ringheterocycle selected from the group consisting of imidazolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl,thiadiazolyl, thiazolinyl, and triazolyl.
 3. A compound according toclaim 2 selected from the group consisting of:(R)-2-{2-[4-(4-benzofuran-2-yl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-benzyloxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-tert-butyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-cyclopentyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2,5-dimethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-(2-{4-[2-(2-ethyl-pyridin-4-yl)-thiazol-4-yl]-phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-ethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(4-ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-ethyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-(4-(2-hydroxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-[2-(4-imidazol-1-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-isopropyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-isopropyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-(4-(2-isopropyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-(2-{4-[2-(4-methoxy-phenyl)-thiazol-4-yl]-phenoxy}ethylamino)-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(5-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-(2-{4-[2-(2-methyl-propane-2-sulfonylmethyl)-thiazol-4-yl]phenoxy}-ethylamino)-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(4-methyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2′-methyl-(2,4′]bithlazolyl-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;(R)-2-[2-(4-oxazol-5-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-phenyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-phenyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(4-phenyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-propyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-3-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-pyridin-4-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-(2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-thiophen-2-yl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(4-p-tolyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-p-tolyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-1H-imidazol-4-yl)-phenoxy]-ethylamino}-ethanol;(R)-1-pyridin-3-yl-2-(2-{4-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-phenoxy}-ethylamino)-ethanol;(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;and(R)-1-pyridin-3-yl-2-{2-[4-(2-trifluoromethyl-thiazol-4-yl)-phenoxy]-ethylamino}-ethanol;a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or stereoisomer.
 4. A compound according to claim 3 selectedfrom the group consisting of:(R)-2-{2-[4-(ethyl-thiazol-2-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methoxymethyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-2-[2-(4-oxazol-4-yl-phenoxy)-ethylamino]-1-pyridin-3-yl-ethanol;(R)-2-{2-[4-(1H-pyrazol-3-yl)-phenoxy]-ethylamino}-1-pyridin-3-yl-ethanol;(R)-1-pyridin-3-yl-2-[2-(4-thiazol-2-yl-phenoxy)-ethylamino]-ethanol;(R)-1-pyridin-3-yl-2-[2-(4-thiazol-4-yl-phenoxy)-ethylamino]-ethanol;and(R)-1-pyridin-3-yl-2-{2-[4-(4-trifluoromethyl-thiazol-2-yl)-phenoxy]-ethylamino}-ethanol;a stereoisomer thereof, or a pharmaceutically acceptable salt of saidcompound or stereoisomer.
 5. A pharmaceutical composition whichcomprises a compound of claim 1, a stereoisomer thereof, or apharmaceutically acceptable salt of said compound or stereoisomer, and apharmaceutically acceptable carrier, vehicle, or diluent.
 6. A method oftreating obesity in a mammal in need of such treatment which methodcomprises administering to said mammal a therapeutically effectiveamount of a compound of claim 1, a stereoisomer thereof, or apharmaceutically acceptable salt of said compound or stereoisomer.
 7. Amethod of treating obesity in a mammal in need of such treatment whichmethod comprises administering to said mammal a therapeutically amountof a composition of claim 5.